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Our research group utilizes the nematode C. elegans to investigate germ cell immortality: mechanisms that allow germ cells remain eternally youthful as they are transmitted from one generation to the next. We also study how telomerase functions at chromosome termini, as well as the consequences of telomere dysfunction.


We have several areas of research interest broadly in the area of immunomodulation using micro/nanoparticles and other carrier systems.  This can include development of traditional vaccines, therapeutic autoimmune vaccines and classic drug delivery platforms targeted to bacterial, viral or parasitic host cells.  To this end, we also seek to develop new materials and platforms optimal for use in modulating immune responses as well as developing scalable production of micro/nanoparticles.


Our laboratory is broadly interested in understanding the molecular mechanisms of transcriptional regulation by cell signaling pathways and the role of pathway cross-talk in cancer biology. In particular, the cAMP signaling cascade directs adaptive cellular responses to a variety of stress stimuli via a combination of acute affects arising from GS-protein coupled receptor (GPCR)-mediated activation of PKA and long-term affects resulting from transcriptional reprogramming directed by CREB and the CREB Regulated Transcription Coactivators (CTRCs). We are applying an interdisciplinary approach to study the consequences of aberrant activation of the cAMP/CREB/CRTC signal circuit on these adaptive responses and how cooperative signaling with other pathways promotes oncogenic processes in oral, head, and neck cancers.


The human body coexists with communities of microbes and bacteria called microbiota, and the balance of these microbes regulates both health and disease. In some cases, imbalances in microbiota have been linked to diseases, such as cancer and diabetes. My group will develop approaches and formulations to deliver specific compounds and microbes to modulate microbiota composition towards healthy states. Other research interests include the development of cell-mediated delivery systems, synthetic cells and nanoparticle drug-delivery systems for applications in vascular disease and cancer.


Laminar organization of neurons in cerebral cortex is critical for normal brain function. Two distinct cellular events guarantee the emergence of laminar organization– coordinated sequence of neuronal migration, and generation of radial glial cells that supports neurogenesis and neuronal migration. Our goal is to understand the cellular and molecular mechanisms underlying neuronal migration and layer formation in the mammalian cerebral cortex. Towards this goal, we are studying the following three related questions: 1. What are the signals that regulate the establishment, development and differentiation of radial glial cells, a key substrate for neuronal migration and a source of new neurons in cerebral cortex?2. What are the signals for neuronal migration that determine how neurons reach their appropriate positions in the developing cerebral cortex?3. What are the specific cell-cell adhesion related mechanisms that determine how neurons migrate and coalesce into distinct layers in the developing cerebral cortex?


Archer, Trevor
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Publications
PHD PROGRAM
Toxicology

Molecular carcinogenesis: cancer, chromatin, transcription, and epigenetics


The Arthur lab is interested in mechanisms by which inflammation alters the functional capabilities of the microbiota, with the long-term goal of targeting resident microbes as a preventative and therapeutic strategy to lessen inflammation and reduce the risk of colorectal cancer. We utilize a unique and powerful in vivo system – germ-free and gnotobiotic mice – to causally link specific microbes, microbial genes, and microbial metabolites with health and disease in the gut.  We also employ basic immunology and molecular microbiology techniques as well as next generation sequencing and bioinformatics to evaluate these essential host-microbe interactions.


Our lab develops new chemistry, and chemical agents as biological probes and drug discovery candidates. Current interests include the discovery of unconventional opioid agents, anti-tuberculosis drugs, and basic biochemistry of androgen biosynthesis inhibitors.


We are interested in studying diabetic vasculopathies. Patients with type 2 diabetes mellitus or metabolic syndrome have aggressive forms of vascular disease, possessing a greater likelihood of end-organ ischemia, as well as increased morbidity and mortality following vascular interventions. Our long term research aims to change the way we treat arterial disease in diabetes by:

  • Understanding why arterial disease is more aggressive in diabetic patients, with a focus in redox signaling in the vasculature.
  • Developing targeted systems using nanotechnology to locally deliver therapeutics to the diseased arteries.

Baldwin, Albert S.
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PHD PROGRAM

Our laboratory studies an amazing regulatory factor known as NF-kappaB. This transcription factor controls key developmental and immunological functions and its dysregulation lies at the heart of virtually all major human diseases.


Batrakova, Elena
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Publications

What if you can target and deliver a drug directly to the side of disease in the body? It is possible, when you use smart living creatures pro-inflammatory response cells, such as monocytes, T-lymphocytes or dendritic cells. You can load these cells with the drug and inject these carriers into the blood stream. They will migrate to the inflammation site (for example, across the blood brain barrier) and release the drug. Thus, you can reduce the inflammation and protect the cells (for example, neurons) in patients with Parkinson’s and Alzheimer diseases.


Blood vessel formation in cancer and development; use mouse culture (stem cell derived vessels) and in vivo models (embryos and tumors); genetic, cell and molecular biological tools; how do vessels assemble and pattern?, dynamic image analysis.


Our lab uses a combination of genetics, high-resolution cellular and animal imaging, animal tumor models and microfluidic approaches to study the problems of cell motility and cytoskeletal organization. We are particularly interested in 1) How cells sense cues in their environment and respond with directed migration, 2) How the actin cytoskeleton is organized at the leading edge of migrating cells and 3) How these processes contribute to tumor metastasis.


Beck, Melinda A.
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PHD PROGRAM
Nutrition

My laboratory studies the relationship between host nutrition and the immune response to infectious disease. Using a mouse model of obesity, we are exploring the mechanism(s) for high mortality from influenza infection in obese mice compared with lean mice. We also have an ongoing clinical research study designed to understand the mechanism(s) involved that impair the influenza vaccine response in obese adults compared with healthy weight adults. We have also demonstrated that host deficiencies in antioxidant nutrients can lead to viral mutations resulting in an avirulent pathogen becoming virulent, suggesting that the host nutritional status can be a driving force for the evolution of viruses.


Dr. Belger’s research focuses on studies of the cortical circuits underlying attention and executive function in the human brain, as well as the breakdown in these functions in neuropsychiatric and neurodevelopment disorders such as schizophrenia and autism. Her research also examines changes in cortical circuits and their physiological properties in individuals at high risk for psychotic disorders. Dr. Belger combines functional magnetic resonance imaging, electrophysiological scalp recording, experimental psychology and neuropsychological assessment techniques to explore the behavioral and neurophysiological dimensions of higher order executive functions. Her most recent research projects have begun focusing on electrophysiological abnormalities in young autistic children and individuals at high risk for schizophrenia.


My research group is broadly interested in the application of sequencing technologies in medical genetics and genomics, using a combination of wet lab and computational approaches.  As a clinician, I am actively involved in the care of patients with hereditary disorders, and the research questions that my group investigates have direct relevance to patient care.  One project uses genome sequencing in families with likely hereditary cancer susceptibility in order to identify novel genes that may be involved in monogenic forms of cancer predisposition.  Another major avenue of investigation examines the use of genome-scale sequencing in clinical medicine, ranging from diagnostic testing to newborn screening, to screening in healthy adults.


Our research focuses on the adhesion mechanisms of platelets and neutrophils to sites of vascular injury/ activation. For successful adhesion, both cell types rely on activation-dependent receptors (integrins) expressed on the cell surface. We are particularly interested in the role of calcium (Ca2+) as a signaling molecule that regulates the inside-out activation of integrin receptors. Our studies combine molecular and biochemical approaches with microfluidics and state-of-the-art in vivo imaging (intravital microscopy) techniques.


Besheer, Joyce
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Publications
PHD PROGRAM
Neurobiology
RESEARCH INTEREST
Behavior, Neurobiology, Pharmacology

Research in my lab examines the neurobiological mechanisms underlying alcoholism and addiction. At present studies are focused on the interaction between stress-related systems and sensitivity to alcohol, in order to better understand the mechanisms that underlie increased alcohol drinking during stressful episodes. We use an array of behavioral (e.g., operant self-administration, drug discrimination) and behavioral pharmacology techniques, including targeted brain regional drug injections, to functionally evaluate the role of specific molecular targets. In parallel to the behavioral studies, we use immunohistochemistry and Western blot techniques to examine alterations in the expression of various molecular targets following stress exposure. We are also applying these techniques to examine and integrate the study of depression that emerges following stress hormone exposure.


Our objective is to understand the dynamic and structural properties of chromosomes during mitosis. We use live cell imaging techniques to address how kinetochores are assembled, capture microtubules and promote faithful segregation of chromosomes.


Boettiger, Charlotte
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Publications
PHD PROGRAM
Neurobiology

My lab uses a cognitive neuroscience approach to understand the neurobiology of drug addiction in humans. The tools we use include fMRI, cognitive testing, physiological monitoring, pharmacology, and genetic testing. We specifically seek to determine 1) how the brain learns new stimulus-response associations and replaces learned associations, 2) the neurobiological mechanisms underlying the tendency to select immediate over delayed rewards, and 3) the neural bases of addiction-related attentional bias.


Our long-term goal is to define the molecular mechanisms of two-component regulatory systems, which are utilized for signal transduction by bacteria, archaea, eukaryotic microorganisms, and plants. Our current focus is to identify and understand the features that control the rates of several different types of protein phosphorylation and dephosphorylation reactions. The kinetics of phosphotransfer reactions can vary dramatically between different pathways and reflect the need to synchronize biological responses (e.g. behavior, development, physiology, virulence) to environmental stimuli. Member of the Molecular & Cellular Biophysics Training Program.


Research in the Bowers lab focuses on investigation of structure activity relationships and mechanisms of action of natural product-derived small molecule therapeutics. We employ a variety of methods to build and modify compounds of interest, including manipulation of natural product biosynthesis, chemical synthesis, and semi-synthesis. One major area of research in the lab is the rationale engineering of biosynthetic pathways to make bacterial drug factories. Compounds targeting transcriptional regulation of cancer as well as multi-drug resistant venereal infections are currently under investigation in the lab.


Our research focuses on understanding the virulence mechanisms of Mycobacterium tuberculosis, the bacterium responsible for the disease tuberculosis.


The Brenman lab studies how a universal energy and stress sensor, AMP-activated protein kinase (AMPK) regulates cellular function and signaling. AMPK is proposed to be a therapeutic target for Type 2 diabetes and Metabolic syndrome (obesity, insulin resistance, cardiovascular disease). In addition, AMPK can be activated by LKB1, a known human tumor suppressor. Thus AMPK signaling is not only relevant to diabetes but also cancer. We are interested in molecular genetic and biochemical approaches to understand how AMPK contributes to neurodegeneration, metabolism/cardiac disease and cancer.


We are interested in the mechanism by which eukaryotic cells are polarized and the role of vesicle transport plays in the determination and regulation of cell polarity and tumorigenesis.


Oscillatory behaviors are seen at multiple scales throughout biology and fundamentally require both a biochemical process capable of sustained, repetitive, state transitions and a system to functionally interpret each state. Multicellular organ systems routinely utilize such biorhythmic electrochemicaloscillators to coordinate and order physiological processes. Or group’s primary research interests are focused on: i) the developmental mechanisms that specify autonomous rhythmic signal generation, and ii) the cellular and biophysical processes that allow for effective downstream transmission of these signals.   To address these topics we combine classical experimental embryological approaches with state-of-the-art live cell imaging to investigate the physiological development of the electrical system of the heart.


Research in the Brouwer laboratory is focused on: (1) hepatic transport of xenobiotics, including mechanisms of uptake, translocation, and biliary excretion; (2) development/refinement of in vitro model systems to predict in vivo hepatobiliary disposition, drug interactions, and hepatotoxicity; (3) influence of disease (e.g., NASH, kidney disease) on hepatobiliary drug disposition; and (4) pharmacokinetics.


Our research group uses several biochemical and structural techniques (e.g. enzyme assays, X-ray crystallography, and cryo-EM) to understand how molecular machines drive the cell cycle. Dysregulation of these enzymes results in numerous cancer types.


The Brustad group is interested in applying chemical principles to expand biological systems beyond Nature’s design. We make use of developing technologies such as unnatural amino acid mutagenesis and non-natural cofactor design to increase the chemical functionality available to proteins. Current efforts are directed towards the genetic incorporation of organocofactor mimics as well as heme protein engineering through the incorporation of orthogonal metalloporphyrin scaffolds. We combine methods in synthetic chemistry, molecular biology, X-ray crystallography, and directed evolution to optimize the function of our protein engineering efforts.


Our lab is interested in the role of chromatin-modifying factors and epigenetics in mammalian development and disease. We are particularly interested in two major areas both of which make use of mouse models: (1) the role of BRG1 and SWI/SNF nucleosome-remodeling complexes in various aspects of hematopoiesis including regulation of globin gene expression and inflammation; (2) the role of dietary fiber and gut microflora on histone modifications, CpG methylation, and prevention of colorectal cancer.


Experimental Evolution of Viruses. We use both computational and experimental approaches to understand how viruses adapt to their host environment. Our research attempts to determine how genome complexity constrains adaptation, and how virus ecology and genetics interact to determine whether a virus will shift to utilizing new host. In addition, we are trying to develop a framework for predicting which virus genes will contribute to adaptation in particular ecological scenarios such as frequent co-infection of hosts by multiple virus strains. For more information, and for advice on applying to graduate school at UNC, check out my lab website www.unc.edu/~cburch/lab.


The UNC Food Allergy Institute (UNCFAI) was established in 2012 to address the growing needs of children and adults with food allergy. Program investigators study the biologic basis of food allergy in the laboratory and in clinical research studies seeking to better understand the role of allergen-specific IgE and the mechanism of allergen immunotherapy. The Institute provides comprehensive, family-centered patient care for food allergy, food-related anaphylaxis, and other related disorders like atopic dermatitis and eosinophilic esophagitis.


Burmeister, Sabrina S.
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Publications
PHD PROGRAM
Biology, Neurobiology

Sensory neurobiology of animal communication, sensory-endocrine interactions and evolution of the brain.


The immune system of severely burned patients becomes extremely suppressed after injury. An overwhelming number of patients die from wound infection and sepsis. However, we are unable to graft these patients with skin from other donors as their immune system is still able to reject the graft efficiently. Our inability to cover the wound site leaves the patients further open to bacterial and fungal infections. Our laboratory investigates the translational immune mechanisms for these devastating consequences of burn within mouse models and burn patients. Focuses in the lab include 1) investigation of innate molecule control of both the innate and adaptive immune systems after burn injury, 2) Role of innate signaling to Damage Associated Molecular Patterns in Immune Dysfunction after burn / inhalational injury,focusing on mTOR-mediated Immunomodulation 3) Using NRF2/KEAP1-Targeted Therapy to Prevent Pneumonitis and Immune Dysfunction After Radiation or Combined Burn-Radiation Injury and 4) Investigating sex-specific disparities in Immune Dysfunction after trauma / transplantation. ​


Our lab is trying to understand the mechanisms by which long noncoding RNAs orchestrate the epigenetic control of gene expression. Relevant examples of this type of gene regulation occur in the case of X-chromosome inactivation and autosomal imprinting. We specialize in genomics, but rely a combination of techniques —  including genetics, proteomics, and molecular, cell and computational biology — to study these processes in both mouse and human stem and somatic cell systems.


Current research projects in the Campbell laboratory include structural, biophysical and biochemical studies of wild type and variant Ras and Rho family GTPase proteins, as well as the identification, characterization and structural elucidation of factors that act on these GTPases. Ras and Rho proteins are members of a large superfamily of related guanine nucleotide binding proteins. They are key regulators of signal transduction pathways that control cell growth. Rho GTPases regulate signaling pathways that also modulate cell morphology and actin cytoskeletal organization. Mutated Ras proteins are found in 30% of human cancers and promote uncontrolled cell growth, invasion, and metastasis. Another focus of the lab is in biochemical and biophysical characterization of the cell adhesion proteins, focal adhesion kinase, vinculin, paxillin and palladin. These proteins are involved in actin cytoskeletal rearrangements and cell motility, amongst other functions. Most of our studies are conducted in collaboration with laboratories that focus on molecular and cellular biological aspects of these problems. This allows us to direct cell-based signaling, motility and transformation analyses. Member of the Molecular & Cellular Biophysics Training Program.


Carelli, Regina M.
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PHD PROGRAM
Neurobiology

Research in the Carelli laboratory is in the area of behavioral neuroscience. Our studies focus on the neurobiological basis of motivated behaviors, including drug addiction. Electrophysiology and electrochemistry procedures are used during behavior to examine the role of the brain ‘reward’ circuit in natural (e.g., food) versus drug (e.g., cocaine) reward. Studies incorporate classical and operant conditioning procedures to study the role of the nucleus accumbens (and dopamine) and associated brain regions in learning and memory, as they relate to motivated behaviors.


A central theme of my work is that I combine engineering and neuroscience with medical research to develop more effective therapies for neurological disease. This leverages my experience as both a clinician scientist and engineer. The passion that drives my career is the search for better ways to prevent and treat epilepsy which affects over 60 million people worldwide.

I lead a long-term effort to define structural and functional biomarkers of epileptic networks and seizure generation to enable more precise diagnostics and effective antiepileptic therapies. Because effective treatment and cure in epilepsy typically require an understanding of neural systems and fundamental processes, my research strives to combine studies of basic questions with applied research. Our goal is to advance the translation of biomedical discoveries into applications that improve clinical outcomes. Although my research spans the continuum from basic to applied questions, it focuses mostly on systems neuroscience and provides a strong scientific basis for implementing antiepileptic strategies. I engage and innovate in the areas of signal processing, computational neuroscience, brain imaging, cell signaling, and gene therapy. Clinical translation is an important goal of my work, in addition to mentoring clinicians and scientists across fields. Involvement of graduate students and postdoctoral fellows is a critical aspect of my research program. Through the research process, I strive to train students in basic concepts, research methodology, management strategies, and philosophies of science. I also take enjoyment from expanding my research program horizons in new areas of the world and with new research questions and technologies.


Gene targeting and state-of-the-art phenotyping methods are used to elucidate the reproductive and cardiovascular roles of the adrenomedullin system and to characterize the novel GPCR-signaling mechanism of Adm’s receptor and RAMP’s.


Molecular evolution and mechanistic enzymology find powerful synergy in our study of aminoacyl-tRNA synthetases, which translate the genetic code. Class I Tryptophanyl-tRNA Synthetase stores free energy as conformational strain imposed by long-range, interactions on the minimal catalytic domain (MCD) when it binds ATP. We study how this allostery works using X-ray crystallography, bioinformatics, molecular dynamics, enzyme kinetics, and thermodynamics. As coding sequences for class I and II MCDs have significant complementarity, we also pursuing their sense/antisense ancestry. Member of the Molecular & Cellular Biophysics Training Program.


Developing and applying novel mass spectrometry (MS)-based proteomics methodologies for high throughput identification, quantification, and characterization of the pathologically relevant changes in protein expression, post-translational modifications (PTMs), and protein-protein interactions. Focuses in the lab include: 1) technology development for comprehensive and quantitative proteomic analysis, 2) investigation of systems regulation in toll-like receptor-mediated pathogenesis and 3) proteomic-based mechanistic investigation of stress-induced cellular responses/effects in cancer pathogenesis.


Our goal is to understand the fundamental cell biology underlying processes such as neurodevelopment, angiogenesis, and the metastasis of cancer cells. Most of our experiments focus on molecular motors such as myosin-X and on the finger-like structures known as filopodia. We generally utilize advanced imaging techniques such as TIRF and single-molecule imaging in conjunction with mammalian cell culture. We also use molecular biology and biochemistry and are in the process of developing a mouse model to investigate the functions of myosin-X and filopodia. We are looking for experimentally driven students who have strong interests in understanding the molecular basis of dynamic cellular processes such as filopodial extension, mechanosensing, and cell migration.


Cross-talk between insulin like growth factor -1 and cell adhesion receptors in the regulation of cardiovascular diseases and complications associated with diabetes.


The Cohen Lab investigates how functional brain networks in humans interact and reconfigure when confronted with changing cognitive demands, when experiencing transformations across development, and when facing disruptions in healthy functioning due to disease. We are also interested in how this neural flexibility contributes to flexibility in control and the ability to learn, as well as the consequences of dysfunction in this flexibility. We use behavioral, neuroimaging, and clinical approaches taken from neuroscience, psychology, and mathematics to address our research questions.


My research aims to uncover the molecular aspects of protein aggregation diseases (also called PAD) which include neurodegenerative diseases (such as Alzheimer’s disease and Amyotrophic Lateral Sclerosis), myofibrillar myopathies (such as muscular dystrophies), as well as the formation of age-related cataracts.  Although very distinct, these disorders share a common underlying pathogenic mechanism.  Using a combination of biochemistry and in vitro approaches, cell biology, and primary cells / transgenic mouse models, we will investigate the post-translational modifications (PTMs) that drive these disease processes. Ultimately, this research will provide a platform for future drug discovery efforts against these devastating diseases.


Lipids are crucial molecules for life. They play important roles in building membranes, storing energy, and cell signaling. We are interested in how lipids move around both within cells and between cells, for example from astrocytes to neurons. The lab uses cutting-edge microscopy techniques including live-cell imaging, superresolution microscopy, and multispectral imaging. We use these approaches to understand how defects in lipid trafficking contribute to metabolic and neurodegenerative diseases.


Our lab is studying the molecular mechanisms which are involved in the induction and proliferation and patterning of cardiac progenitor cell populations. To identify the molecular pathways involved in these processes, we have used Xenopus and mouse as model systems with particular focus on the endogenous role of genes implicated in the early steps of cardiogenesis and human congenital heart disease. Present projects in the lab involve embryological manipulations, tissue explant cultures, molecular screens as well as protein-DNA interaction experiments, biochemistry and promoter analysis.


My lab is focused on the improvement of treatment of chronic bacterial infections. We aim to determine the mechanisms of antibiotic tolerance. Our aim is to understand the physiology of the bacterial cell, primarily Staphylococcus aureus, during infection and how this physiology allows the cell to survive lethal doses of antibiotic. We will use advanced methods such as single cell analysis and Tn-seq to determine the factors that facilitate survival in the antibiotic’s presence. Once we understand this tolerance, we will develop advanced screens to identify novel compounds that can be developed into therapeutics that can kill these drug tolerant “persister” cells and eradicate deep-seated infections.


The Cook lab studies the major transitions in the cell division cycle and how perturbations in cell cycle control affect genome stability. We have particular interest in mechanisms that control protein abundance and localization at transitions into and out of S phase (DNA replication phase) and into an out of quiescence. We use a variety of molecular biology, cell biology, biochemical, and genetic techniques to manipulate and evaluate human cells as they proliferate or exit the cell cycle. We collaborate with colleagues interested in the interface of cell cycle control with developmental biology, signal transduction, DNA damage responses, and oncogenesis.


The primary research area my lab is the regulation of meiotic recombination at the genomic level in higher eukaryotes. Genomic instability and disease states, including cancer, can occur if the cell fails to properly regulate recombination. We have created novel tools that give our lab an unparalleled ability to find mutants in genes that control recombination. We use a combination of genetics, bioinformatics, computational biology, cell biology and genomics in our investigations. A second research area in the lab is the role of centromere DNA in chromosome biology. We welcome undergraduates, graduate students, postdoctoral fellows and visiting scientists to join our team.


The main research project is to determine the role of intercellular junctions in normal development, cell aging and cataract formation in human and animal lenses.


Dr. Cotter’s research is aimed at understanding molecular mechanisms of bacterial pathogenesis. Using Bordetella species as models, her group is studying the role of virulence gene regulation in respiratory pathogenesis, how virulence factors activate and suppress inflammation in the respiratory tract, and how proteins of the Two Partner Secretion pathway family are secreted to the bacterial surface and into the extracellular environment. A second major project is focused on Burkholderia pseudomallei, an emerging infectious disease and potential biothreat agent. This research is aimed at understanding the role of autotransporter proteins in the ability of this organism to cause disease via the respiratory route.


Our lab is interested in molecular mechanisms of oncogenesis, specifically as regulated by Ras and Rho family small GTPases. We are particularly interested in understanding how membrane targeting sequences of these proteins mediate both their subcellular localization and their interactions with regulators and effectors. Both Ras and Rho proteins are targeted to membranes by characteristic combinations of basic residues and lipids that may include the fatty acid palmitate as well as farnesyl and geranylgeranyl isoprenoids. The latter are targets for anticancer drugs; we are also investigating their unexpectedly complex mechanism of action. Finally, we are also studying how these small GTPases mediate cellular responses to ionizing radiation – how do cells choose whether to arrest, die or proliferate?


The Cyr laboratory studies cellular mechanisms for cystic fibrosis and prion disease. We seek to determine how protein misfolding leads to the lung pathology associated with Cystic Fibrosis and the neurodegeneration associated with prion disease.


The work in our laboratory is focused on understanding the molecular pathogenesis of Kaposi’s sarcoma-associated herpesvirus (KSHV), an oncogenic human virus. KSHV is associated with several types of cancer in the human population. We study the effect of KSHV viral proteins on cell proliferation, transformation, apoptosis, angiogenesis and cell signal transduction pathways. We also study viral transcription factors, viral replication, and the interactions of KSHV with the human innate immune system. Additionally, we are developing drug therapies that curb viral replication and target tumor cells.


We use the premier model plant species, Arabidopsis thaliana, and real world plant pathogens like the bacteria Pseudomonas syringae and the oomycete Hyaloperonospora parasitica to understand the molecular nature of the plant immune system, the diversity of pathogen virulence systems, and the evolutionary mechanisms that influence plant-pathogen interactions. All of our study organisms are sequenced, making the tools of genomics accessible.


Research in the Darville lab is focused on increasing our understanding of immune signaling pathways active in development of genital tract disease due to Chlamydia trachomatis and determination of chlamydial antigen-specific T cell responses that lead to protection from infection and disease. In vitro, murine model, and human studies are being performed with the ultimate goal to develop a vaccine against this prevalent sexually transmitted bacterial pathogen. Genetic and transcriptional microarray studies are being performed to explore pathogenic mechanisms and determine biomarkers of pelvic inflammatory disease due to Chlamydia as well as other sexually transmitted pathogens.


With a particular interest in pediatric solid tumors, our lab aims to develop a mechanistic understanding of the role of aberrant or dysregulated transcription factors in oncogenesis.


Our lab studies brain network connectivity in the healthy brain and in neurological and neuropsychiatric patient populations. We focus on the organizational, dynamical, and computational properties of large-scale brain networks and determine how these properties contribute to human behavior in health and disease. We strive to advance the basic understanding of brain structure and function, while making discoveries that can be translated to clinical practice.


Our research focuses on the immunological aspects of pathogen-host interactions. The lab is actively involved in HIV pathogenesis and vaccine studies using the nonhuman primate model of SIV infection. We are particularly interested in pediatric HIV transmission by breast-feeding and the early, local host immune response. A main research focus is on developmental differences in host immune responses between infants and adults and how they alter pathogenesis. The effect of co-infections (e.g. malaria and Tb) on HIV pathogenesis and transmission is a second research focus. The lab is developing a nonhuman primate model of SIV-Plasmodium fragile co-infection to study HIV-P. falciparum infection in humans.


We study Borrelia burgdorferi (the agent of Lyme disease) as a model for understanding arthropod vector-borne disease transmission. We also study the epidemiology and pathogenesis of dengue viruses associated with hemorrhagic disease.


Our research centers on understanding the molecular basis of human carcinogenesis. In particular, a major focus of our studies is the Ras oncogene and Ras-mediated signal transduction. The goals of our studies include the delineation of the complex components of Ras signaling and the development of anti-Ras inhibitors for cancer treatment. Another major focus of our studies involves our validation of the involvement of Ras-related small GTPases (e.g., Ral, Rho) in cancer. We utilize a broad spectrum of technical approaches that include cell culture and mouse models, C. elegans, protein crystallography, microarray gene expression or proteomics analyses, and clinical trial analyses.


We study how mammalian cells regulate their survival and death (apoptosis). We have focused our work on identifying unique mechanisms by which these pathways are regulated in neurons, stem cells, and cancer cells. We utilize various techniques to examine this in primary cells as well as in transgenic and knock out mouse models in vivo. Our ultimate goal is to discover novel cell survival and death mediators that can be targeted for therapy in neurodegeneration and cancer.


DeSimone, Joseph M.
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Publications
PHD PROGRAM
Chemistry, Pharmacology

The direct fabrication and harvesting of monodisperse, shape-specific nano-biomaterials are presently being designed to reach new understandings and therapies in cancer prevention, diagnosis and treatment.  Students interested in a rotation in the DeSimone group should not contact Dr. DeSimone directly.  Instead please contact Chris Luft at jluft@email.unc.edu.


The work focuses on how air pollutants affect human health, the role of genetics and epigenetic factors in determining susceptibility and clinical/dietary strategies to mitigate these effects. There is a strong emphasis on translational research projects using a multi-disciplinary approach. Thus, by using human in vivo models (such as clinical studies) we validate in vitro, epidemiology, and animal findings.


Sleep is an essential and evolutionarily conserved process that modifies synapses in the brain to support cognitive functions such as learning and memory. We are interested in understanding the molecular mechanisms of synaptic plasticity with a particular interest in sleep. Using mouse models of human disease as well as primary cultured neurons, we are applying this work to understanding and treating neurodevelopmental disorders including autism and intellectual disability. The lab focuses on biochemistry, pharmacology, animal behavior and genetics.


Our lab tries to understand viral pathogenesis. To do so, we work with two very different viruses – West Nile Virus (WNV) and Kaposi¹s sarcoma-associated herpesvirus (KSHV/HHV-8).


We study host defense mechanisms in the lungs, particularly the inflammatory and innate immune processes important in the pathogenesis and course of bacterial pneumonia, acute lung injury/acute respiratory distress syndrome, and cigarette smoke-associated lung disease. Basic and translational studies address mechanisms of host defense, including recruitment and function of leukocytes, vascular permeability leading to edema, bacterial clearance and resolution.  Cell signaling pathways initiated by binding of leukocyte-endothelial cell adhesion molecules and molecular mechanisms underlying the functions of neutrophils are two particular areas.


We use an integrated approach (genomics, proteomics, computational biology) to study the molecular mechanisms of hormone and drug desensitization. Our current focus is on RGS proteins (regulators of G protein signaling) and post-translational modifications including ubiquitination and phosphorylation.


My lab studies how genes function within the three-dimensional context of the nucleus to control development and prevent disease. We combine genomic approaches (ChIP-Seq, ChIA-PET) and genome editing tools (CRISPR) to study the epigenetic mechanisms by which transcriptional regulatory elements control gene expression in embryonic stem cells.  Our current research efforts are divided into 3 areas: 1) Mapping the folding pattern of the genome 2) Dynamics of three-dimensional genome organization as cells differentiate and 3) Functional analysis of altered chromosome structure in cancer and other diseases.


Dudek, Serena M.
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Publications
PHD PROGRAM
Neurobiology
RESEARCH INTEREST
Neurobiology

Humans have a remarkable ability to learn from their environment after birth, but this plasticity also makes them susceptible to environmental insults.  At the cellular level, learning is accomplished by changing the strength of the synaptic connections between neurons.  Therefore, the Dudek lab is working to identify the underlying processes of synaptic plasticity.  Using molecular techniques, patch clamp recordings and confocal microscopic imaging from neurons in brain slices and culture, we ask how neuronal activity controls gene transcription and brain circuitry and what determines why some brain regions are more plastic than others.  These studies are likely to shed light on environmental causes of psychiatric diseases such as schizophrenia and autism.


My lab studies a recently identified pathogen-sensing signaling complex known as the inflammasome. The inflammasome is responsible for the proteolytic maturation of some cytokines and induces a novel necrotic cell death program. We have found that critical virulence factors from certain pathogens are able to activate NLRP3-mediated signaling, suggesting these pathogens may exploit this host signaling system in order to promote infections.  Our lab has active research projects in several areas relating to inflammasome signaling ranging from understanding basic molecular mechanisms of the pathway to studying the role of the system in animal models of infectious diseases.


My lab studies how cell proliferation is controlled during animal development, with a focus on the genetic and epigenetic mechanisms that regulate DNA replication and gene expression throughout the cell cycle. Many of the genes and signaling pathways that we study are frequently mutated in human cancers. Our current research efforts are divided into three areas:  1) Plasticity of cell cycle control during development  2) Histone mRNA biosynthesis and nuclear body function  3) Epigenetic control of genome replication and function


The Elston lab is interested in understanding the dynamics of complex biological systems, and developing reliable mathematical models that capture the essential components of these systems. The projects in the lab encompass a wide variety of biological phenomena including signaling through MAPK pathways, noise in gene regulatory networks, airway surface volume regulation, and understanding energy transduction in motor proteins. A major focus of our research is understanding the role of molecular level noise in cellular and molecular processes. We have developed the software tool BioNetS to accurately and efficiently simulate stochastic models of biochemical networks


Our lab applies cutting edge genetic and proteomic technologies to unravel dynamic signaling networks involved in cell proliferation, genome stability and cancer. These powerful technologies are used to systematically interrogate the ubiquitin proteasome system (UPS), and allow us to gain a systems level understanding of the cell at unparalleled depth. We are focused on UPS signaling in cell cycle progression and genome stability, since these pathways are universally perturbed in cancer.


The research in my lab is divided into two main areas – 1) Atomic force microscopy and fluorescence studies of protein-protein and protein-nucleic acid interactions, and 2) Mechanistic studies of transcription elongation. My research spans the biochemical, biophysical, and analytical regimes.


Yeast molecular genetics; MAP-Kinease activation pathways; regulation of cell differentiation.


As the Director of the UNC Kidney Center, the scope of Dr. Falk’s research interests spans many disciplines, including molecular biology, immunology, genetics, pathology, cell biology, protein chemistry, epidemiology, pharmacokinetics and biostatistics. Dr. Falk is recognized world wide as a leader in research on kidney diseases related to autoimmune responses. He works closely with the basic research scientists within the UNC Kidney Center, including Dr. Gloria Preston, thus this research program provides an environment for Translational Research within the UNC Kidney Center.


Air pollution exposure is associated with increased hospital visits and mortality, and is a major area of research for the United States Environmental Protection Agency.  The primary research interest of my laboratory is the examination of the effects and mechanisms of air pollutants in the environment on normal cardiopulmonary function (cardiac toxicology), particularly in models of cardiovascular disease, using state-of-the-art targeted and high throughput methods. Research findings are often used to inform environmental public health and contribute to the refinement of the US EPA’s National Ambient Air Quality Standards for specific air pollutants set to limit their health impact.


The Reproductive Endocrinology Group in the National Toxicology Program (NTP) Labs, led by Dr. Fenton, focuses on the role of environmental chemicals in breast developmental timing as it relates to puberty, increased susceptibility to form breast tumors, altered lactational ability, and the effects of chemicals on independent breast cancer risk factors such as obesity, breast density and pubertal timing. The projects within the lab often take a systems biology approach to the problem and instead of delving into exact mechanisms of an insult, which is in line with the missions of the NTP. The group also provides expertise in the use of whole mount mammary gland preparations in evaluating early life development of both male and female rat offspring and lifelong effects in female mice.


Fessler laboratory investigates mechanisms of the innate immune response, in particular Toll like Receptor (TLR) pathways and how they regulate inflammatory and host defense responses in the lung.  To this end, we use both in vitro (macrophage cultures) and in vivo (mouse models of acute lung injury and pneumonia) model systems, and also use translational approaches (e.g., studies using human peripheral blood leukocytes and alveolar macrophages).  An area of particular interest within the laboratory is defining how cholesterol trafficking and dyslipidemia innate immunity.


Our lab studies the underlying structural and functional substrates of behavior in disease using rodent models. Specifically our goal is to develop a better understanding of how cellular function in the CNS is affected by drug-related substances (opioids, cannabinoids) in the context of HIV infection. That includes the study of how drugs of abuse exacerbate the pathogenesis of neuroAIDS but also the study of targets within the endocannabinoid system for the potential treatment of HIV. We use various in vivo and in vitro techniques, including primary cell culture models, behavioral conditioning tasks, live cell imaging, and electrophysiology.


Research interests include: transport processes in the lung, flow and structure of nano-materials & macromolecular fluids, weakly compressible transport phenomena, solitons and optical fiber applications, inverse problems for material characterization and modeling of transport in multiphase porous media.


My lab has a long-standing interest in gene regulation, epigenetics, chromatin and RNA biology, especially as it pertains to cancer. We are interested in studying the formation and function of transcriptional enhancers and the non-coding RNAs that are actively produced at enhancers, known as enhancer RNAs, which are involved in modulating several aspects of gene regulation. In addition, we aim to understand how transcriptional enhancers help orchestrate responses to external stimuli found in the tumor microenvironment. We address these research aims by using an interdisciplinary approach that combines molecular and cellular techniques with powerful genomic and computational approaches.


Our goal is to revolutionize the treatment of psychiatric and neurological illness by developing novel brain stimulation paradigms. We identify and target network dynamics of physiological and pathological brain function. We combine computational modeling, optogenetics, in vitro and in vivo electrophysiology in animal models and humans, control engineering, and clinical trials. We strive to make our laboratory a productive, collaborative, and happy workplace.


Fry, Rebecca
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Publications
PHD PROGRAM
Toxicology
RESEARCH INTEREST
Genetics, Systems Biology, Toxicology

The lab focuses on understanding how environmental exposures are associated with human disease with a particular focus on genomic and epigenomic perturbations. Using environmental toxicogenomics and systems biology approaches, we aim to identify key molecular pathways that associate environmental exposure with diseases. A current focus in the lab is to study prenatal exposure to various types of metals including arsenic, cadmium, and lead. We aim to understand molecular mechanisms by which such early exposures are associated with long-term health effects in humans. For example, we are examining DNA methylation (epigenetic) profiles in humans exposed to metals during the prenatal period. This research will enable the identification of gene and epigenetic biomarkers of metal exposure. The identified genes can serve as targets for study to unravel potential molecular bases for metal-induced disease. Ultimately, we aim to identify mechanisms of metal -induced disease and the basis for inter-individual disease susceptibility.


The Furey Lab is interested in understanding gene regulation processes in specific cell types, especially with respect to complex phenotypes, and the effect of genetic and environmental variation on gene regulation. We have explored these computationally by concentrating on the analysis of genome-wide open chromatin data generated from high-throughput sequencing experiments; and the development of statistical methods and computational tools to investigate underlying genetic and biological mechanisms of complex phenotypes. Our current projects include determining the molecular effects of exposure to 1,3-butadiene, a known carcinogen, on chromatin, gene regulation, and gene expression in lung, liver, and kidney tissues of genetically diverse mouse strains. We are also exploring chromatin, transcriptional, and microbial changes in inflammatory bowel diseases to identify biomarkers of disease onset, severity, and progression.


Over millions of years of coexistence humans and pathogens have develop intricate and very intimate relationships.  These highly specialized interactions are the basic determinants of pathogenesis and disease progression.  Our laboratory is interested in elucidating the molecular basis of disease.  Our multidisciplinary approach to molecular medicine is based on our interest in the translation of basic research observations into clinical implementation.  For this purpose we use a variety of in vitro and in vivo approaches to study AIDS, Cancer, immunological diseases, gene therapy, etc.  Of particular interest is the use of state of the art models such as humanized mice to study human specific pathogens like HIV, EBV, Kaposiâ’s sarcoma, influenza, xenotropic murine leukemia virus-related virus.  In addition, we are interested in the development and implementation of novel approaches to prevent viral transmission using pre-expossure prophylaxis and vaccines.


As a pediatric neurologist and brain tumor researcher, I seek to understand the link between brain growth and childhood brain tumors.  During postnatal cerebellar development, neural progenitors divide rapidly.  This wave of neurogenesis must be strictly controlled to prevent formation of medulloblastoma, a malignant neuroblastic tumor of the cerebellum.  Using transgenic mice that express constitutively active Smoothened, we are able to recapitulate tumorigenesis in mice.  These tumor-prone mice develop medulloblastomas that model the human tumor in pathology and gene expression.  We use this primary brain tumor model to gain novel insight into medulloblastoma pathogenesis and treatment.


Dr. Gilmore’s research group is applying state-of–the-art magnetic resonance imaging and image analysis techniques to study human brain development in 0-6 year olds.  Approaches include structural, diffusion tensor, and resting state functional imaging, with a focus on cortical gray and white matter development and its relationship to cognitive development.  Studies include normally developing children, twins, and children at high risk for schizophrenia and bipolar illness.  We also study the contributions of genetic and environmental risk factors to early brain development in humans.  A developing collaborative project with Flavio Frohlich, PhD will use imaging to study white and gray matter development in ferrets and its relationship with cortical oscillatory network development.


Dr M Ian Gilmour is a Principal Investigator at the National Health and Environmental Effects Research Laboratory (NHEERL), U.S Environmental Protection Agency in RTP.    He received an Honors degree in microbiology from the University of Glasgow, and a doctorate in aerosol science and mucosal immunology from the University of Bristol in 1988.  After post-doctoral work at the John Hopkins School of Public Health and the U.S. EPA, he became a Research Associate in the Center for Environmental Medicine at the University of North Carolina. In 1998 he joined the EPA fellowship program and in 2000 became a permanent staff member.  He holds adjunct faculty positions with the UNC School of Public Health and the Curriculum in Toxicology, and at NC State Veterinary School.  He has published over 80 research articles in the field of pulmonary immunobiology where his research focuses on the interaction between air pollutant exposure and the development of infectious and allergic lung disease.


Giovanello, Kelly S.
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Publications
PHD PROGRAM
Neurobiology

My research combines behavioral, patient-based, and functional neuroimaging approaches to investigate the cognitive neuroscience of human learning and memory. My primary research focus is in elucidating the cognitive processes and neural mechanisms mediating relational memory – the form of memory which represents relationships among items or informational elements. In everyday life, relational memory processes play a critical role in linking or binding together the various cognitive, affective, and contextual components of a learning event into an integrated memory trace. I am interested in exploring the cognitive and neural processes mediating relational memory in young adults and examining how these processes change with healthy aging and neurodegenerative disease (particularly Alzheimer’s disease).


I have been an NIH-funded women’s health researcher for over 20 years. The focus of my current research is in reproductive mood disorders, such as premenstrual dysphoric disorder and postpartum depression. Current research in my lab is investigating the role of psychosocial stress (e.g., histories of trauma) and alterations in cardiovascular, neuroendocrine, and GABAergic neurosteroid reactivity to stress in reproductive mood disorders.   I also have a long-standing research record in studies investigating ethnic and racial differences in physiologic stress reactivity and endogenous pain regulation.    /  / I co-direct an NIH-funded postdoctoral training program as well as the UNC Department of Psychiatry Junior Faculty Mentoring Program.  I am dedicated to training the next generation of independent investigators.


During development transcriptional and posttranscriptional networks are coordinately regulated to drive organ maturation, tissue formation, and cell fate. Interestingly, more than 90% of the human genes undergo alternative splicing, a posttranscriptional mechanism that explains how one gene can give rise to multiple protein isoforms. Heart and skeletal muscle are two of the tissues where the most tissue specific splicing takes place raising the question of how developmental stage- and tissue-specific splicing influence protein function and how this regulation occurs. In my lab we are interested on two exciting aspects of this broad question: i) how alternative splicing of trafficking and membrane remodeling genes contributes to muscle development, structure, and function, ii) the coupling between epigenetics and alternative splicing in postnatal heart development.


We study large multinucleate cells such as fungi, muscle and placenta to understand how cells are organized in time and space.  Using quantitative live cell microscopy, biochemical reconstitution and computational approaches we examine how the physical properties of molecules generate spatial patterning of cytosol and scaling of cytoskeleton scaffolds in the cell cycle.


Successful respiratory pathogens must be able to respond swiftly to a wide array of sophisticated defense mechanisms in the mammalian lung.  In histoplasmosis, macrophages — a first line of defense in the lower respiratory tract — are effectively parasitized by Histoplasma capsulatum.  We are studying this process by focusing on virulence factors produced as this “dimorphic” fungus undergoes a temperature-triggered conversion from a saprophytic mold form to a parasitic yeast form.  Yersinia pestis also displays two temperature-regulated lifestyles, depending on whether it is colonizing a flea or mammalian host.  Inhalation by humans leads to a rapid and overwhelming disease, and we are trying to understand the development of pneumonic plague by studying genes that are activated during the stages of pulmonary colonization.


We address fundamental issues in cell and developmental biology, issues such as how cells move to specific positions, how the orientations of cell divisions are determined, how the mitotic spindle is positioned in cells, and how cells respond to cell signaling – for example Wnt signaling, which is important in development and in cancer biology. We are committed to applying whatever methods are required to answer important questions. As a result, we use diverse methods, including methods of cell biology, developmental biology, forward and reverse genetics including RNAi, biochemistry, biophysics, mathematical and computational modeling and simulations, molecular biology, and live microscopy of cells and of the dynamic components of the cytoskeleton – microfilaments, microtubules, and motor proteins. Most experiments in the lab use C. elegans embryos, and we have also used Drosophila and Xenopus recently. C. elegans is valuable as a model system because of the possibility of combining the diverse techniques above to answer a wide array of interesting questions. We also have a project underway to develop a new model system for studying how cellular and developmental mechanisms evolve, using little-studied organisms called water bears. Rotating graduate students learn to master existing techniques, and students who join the lab typically grow their rotation projects into larger, long term projects, and/or develop creative, new projects.


Our primary research is in the area of computational systems biology, with particular interest in the study of biological signaling networks; trying to understand their structure, evolution and dynamics. In collaboration with wet lab experimentalists, we develop and apply computational models, including probabilistic graphical and multivariate methods along with more traditional engineering approaches such as system identification and control theory, to current challenges in molecular biology and medicine. Examples of recent research projects include: prediction of protein interaction networks, multivariate modeling of signal transduction networks, and development of methods for integrating large-scale genomic data sets.


We are a human immunology lab focusing on all aspects of T cell immunobiology in HIV-1 infection. Studies range from basic questions like, ‘What are the determinants of the first T cell response following infection?’ to translational challenges such as ‘What is the best design for a T cell vaccine to either prevent infection or achieve HIV-1 cure?’

Keywords: T cells, HIV-1, Escape, CD8 T cells, Vaccines, Cure, Vaccines


Gordon-Larsen’s work integrates biology, behavior, and environment to understand, prevent and treat obesity, cardiovascular and cardiometabolic diseases. She works with biomarker, microbiome, metabolome, genetic, weight, diet, and environment data using multilevel modeling and pathway-based analyses. She works with several longitudinal cohorts that span more than 30 years. Most of her work uses data from the US and China. Her research teams include a wide variety of scientists working in areas such as genetics, medicine, bioinformatics, biostatistics, microbiology, nutrition, and epidemiology.


Our research goal is to understand how bacterial pathogens cause disease on their hosts. We are working with a plant pathogen, Pseudomonas syringae which introduces virulence proteins into host cells to suppress immune responses. Our laboratory collaborates with Jeff Dangl’s lab in the UNC Biology Department using genomics approaches to identify P. syringae virulence proteins and to discover how they alter plant cell biology to evade the plant immune system and cause disease.


Our lab is studying the role of mitogen and stress-activated protein kinases to regulate key aspects of cell metabolism. We are also studying signalling by tyrosine kinases in response to toxicological agents or cell stress.


We are interested in basic DNA-protein interactions as related to – DNA replication, DNA repair and telomere function.  We utilize a combination of state of the art molecular and biochemical methods together with high resolution electron microscopes.


My group develops and deploys computational tools to predict physiological function and dysfunction. We are interested in a range of applications in medicine and biology, but our primary focus is the cardiovascular system. My group is actively developing fluid-structure interaction (FSI) models of the heart, arteries, and veins, and of cardiovascular medical devices, including bioprosthetic heart valves, ventricular assist devices, and inferior vena cava filters. We are also validating these models using in vitro and in vivo approaches. We also model cardiac electrophysiology and electro-mechanical coupling, with a focus on atrial fibrillation (AF), and aim to develop mechanistically detailed descriptions of thrombosis in AF. This work is carried out in collaboration with clinicians, engineers, computer and computational scientists, and mathematical scientists in academia, industry, and regulatory agencies.


During cell shape change and motility, a dynamic cytoskeleton produces the force to initiate plasma membrane protrusion, while vesicle trafficking supplies phospholipids and membrane proteins to the expanding plasma membrane. Extracellular cues activate intracellular signaling pathways to elicit specific cell shape changes and motility responses through coordinated cytoskeletal dynamics and vesicle trafficking. In my lab we are investigating the role of two ubiquitin ligases, TRIM9 and TRIM67, in the cell shape changes that occur during neuronal development. We utilize a variety techniques including high resolution live cell microscopy, gene disruption, mouse models, and biochemistry to understand the complex coordination of cytoskeletal dynamics and membrane trafficking driving neuronal shape change and growth cone motility in primary neurons.


Dynamic control of signaling networks in living cells; Rho family and MAPK networks in motility and network plasticity; new tools to study protein activity in living cells (i.e., biosensors, protein photomanipulation, microscopy). Member of the Molecular & Cellular Biophysics Training Program and the Medicinal Chemistry Program.


My lab studies a gene silencing phenomenon called RNA interference, or RNAi.  We are interested in the role of RNAi in regulating endogenous genes, particularly those involved in cancer progression pathways.


My research focus centers on retinal gene/drug therapy using nanotechnologies. My laboratory is interested in developing gene therapies for inherited blinding diseases and eye tumors. We are particularly interested in understanding the gene expression patterns that are regulated by the cis-regulatory elements. We utilize compacted DNA nanoparticles which have the ability to transfer large genetic messages to overcome various technical challenges and to appreciate the translational potential of this technology. This multidimensional technology also facilitated targeted drug delivery. Currently, we are working on the design and development of several specific nano formulations with targeting, bioimaging and controlled release specificities.


Current research indicates that inflammatory bowel diseases (IBD’s), including Crohn’s disease and ulcerative colitis, are due to uncontrolled innate and adaptive immune responses to commensal (non-pathogenic) intestinal bacteria in genetically susceptible hosts.  However, the roles of intestinal bacteria in the perpetuation and progression of IBD’s are unclear and the effects of intestinal inflammation on commensal bacterial physiology and virulence are unknown.  We hypothesize that commensal bacteria dynamically respond to intestinal inflammation in a manner that perpetuates or worsens disease.  Exploring this hypothesis will enhance our understanding of the pathogenesis of IBD’s and host-microbial interactions, and potentially identify new therapeutic targets for these currently incurable diseases.


The Neurotoxicology Group examines the role of microglia interactions with neurons and the associated immune-mediated responses in brain development and aging as they relate to the initiation of brain damage, the progression of cell death, and subsequent repair/regenerative capabilities.  We have an interest in the neuroimmune response with regards to neurodegenerative diseases such as, Alzheimer’s disease.


The Hathaway lab is focused on understanding the biological events responsible for dynamically regulating the selective expression of the mammalian genome. In multicellular organisms, genes must be regulated with high precision during stem cell differentiation to achieve normal development. Pathologically, the loss of proper gene regulation caused by defects in chromatin regulatory enzymes has been found to be a driving force in cancer initiation and progression. My lab uses a combination of chemical biology and cell biology approaches to unravel the molecular mechanisms that govern gene expression. We utilize new tools wielding an unprecedented level of temporal control to visualize changes in chromatin structure and function in mammalian cells and animal models. In addition, we seek to identify small molecule inhibitors that are selective for chromatin regulatory enzymes with the potential for future human therapeutics.


Research in my laboratory focuses on the effects of air pollution and other environmental pollutants on the cardiovascular and respiratory systems. We use both traditional as well as novel physiological approaches (radiotelemetry, HF echocardiography, physiological challenge testing) to determine not only the short-term effects of exposure, but also the long-term consequences on health, particularly in the development of chronic diseases (e.g. heart disease). Rodent models are used to study the effects of real-world air pollution concentrations on the central and local neural controls of the cardiovascular and respiratory systems that render a host susceptible to adverse health events. Newer exciting research is focused on public health aspects such as nutrition (e.g. vitamin deficiencies) and non-environmental stressors (e.g. noise, climate change, social disruption) as modifiers of air pollution health effects. These studies examine the epigenetic changes that occur in early life or during development that result in physiological effects and future susceptibility.


Hedrick, Tyson
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Publications
PHD PROGRAM
Biology

Research in my laboratory focuses on how animals produce and control movement, with a particular interest in animal flight.  We use both computational and experimental techniques to examine how organismal components such as the neuromuscular and neurosensory systems interact with the external environment via mechanics and aerodynamics to produce movement that is both accurate and robust.  Keywords: biomechanics, flight, avian, insect, neural control, muscle, locomotion, computational modeling.


We study alphavirus infection to model virus-induced disease.  Projects include 1) mapping viral determinants involved in encephalitis, and 2) using a mouse model of virus-induced arthritis to identify viral and host factors associated with disease.


Hemminger, Brad
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Publications
RESEARCH INTEREST
Bioinformatics

bioinformatics, scholarly communications, digital libraries, user interface design, annotation, virtual environments, medical informatics, databases and datamining.


My research interests involve the structure of inhibitory neuronal networks and how these networks change to produce adverse behavioral outcomes. My main interest is how the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) regulates neuronal networks via both synaptic and extrasynaptic forms of inhibition and how alterations in inhibitory networks contribute to clinical conditions such as alcohol use disorder, nicotine, addiction, or stress. My work has focused primarily on three brain regions: the nucleus tractus solitaries (NTS), central and basolateral amygdala, and ventral tegmental area. In each of these areas I have identified local inhibitory networks that control overall excitability and that are dysregulated by exposure to acute and or chronic exposure to alcohol or nicotine.


Research in the Hicks lab focuses on development and implementation of mass spectrometric approaches for protein characterization including post-translational modifications, as well as the identification of bioactive peptides/proteins from plants. Keywords: proteins / peptides, proteomics, PTM, enzymes, analytical chemistry, mass spectrometry, separations / chromatography, plants, algae.


Flexibility of the brain allows the same sensory cue to have very different meaning to the animal depending on past experience (i.e. learning and memory) or current context. Our goal is to understand this process at the levels of synaptic plasticity, neural circuit and behavior. Our model system is a simple brain of the fruit fly, Drosophila. We employ in vivo electrophysiology and two-photon calcium imaging together with genetic circuit manipulation. Taking advantage of this unique combination, we aim to find important circuit principles that are shared with vertebrate systems.

 


Imagine a naturally intelligent therapy that can seek out and destroy cancer cells like no other available treatment.  In the Hingtgen Lab, we are harnessing Nobel Prize-winning advancements to create a new type of anti-cancer treatment: personalized stem cell-based therapies.  We use a patient’s own skin sample and morph it into cells that chase down and kill cancer. We take advantage of a little-known aspect of stem cells- they can home in on cancer by picking up a signal through receptors on the cell surface. All the while, the therapeutic stem cells are pumping out potent anti-cancer drugs that selectively kill any cancer cell nearby while leaving the healthy brain unharmed. Our initial studies focused on aggressive brain cancers, however we quickly expanded our testing to a variety of cancer types. Working at the interface of basic science and human patient testing, our ultimate goal is to translate this novel approach into the clinical setting where it can re-define treatment for cancers that currently have no effective treatment options.


Our lab works with adeno-associated viral vectors for both the characterization of vector and host responses upon transduction and as therapeutic agents for the treatment of genetic diseases.  In particular, we tend to focus on the 145 nucleotide viral inverted terminal repeats of the transgenic genome and their multiple functions including the replication initiation, inherent promoter activity, and stimulation of intra/inter molecular DNA repair pathways.  The modification of the AAV ITRs by synthetic sequences imparts unique functions/activities rendering these synthetic vectors perhaps better suited for therapeutic applications.


My research interest is in genomic characterization and integrative genomic approaches to better understand cancer. My group is part of the NCI Genome Data Analysis Center focused on RNA expression analysis. We have a number of ongoing projects including developing molecular classifications for potential clinical utility, developing methods for deconvolution to understand bulk tissue heterogeneity, analysis of driver negative cancers, and analysis of ancestry markers with cancer features.


Our preclinical research is based on the concept that drugs of abuse gain control over behavior by hijacking molecular mechanisms of neuroplasticity within brain reward circuits. To understand this process, we take a multidisciplinary preclinical approach that combines state-of-the-art behavioral methods with a variety of molecular, genetic, and pharmacological approaches. Members of our lab are dedicated to helping win the war on addiction by identifying targets of alcohol within brain reward circuits and validating compounds for potential pharmacotherapeutic impact. Our preclinical research employs several cutting-edge approaches to identify neural targets of voluntary alcohol self-administration in mice, including 2D-DIGE proteomics, Western blots, and immunohistochemistry. We evaluate neural circuits using track tracing, optogenetics, and site-specific microinjection strategies, and have plans to conduct fMRI in mice. To evaluate mechanistic regulation of behavioral pathologies in addiction, we employ knockout mice, viral vectors, and pharmacological approaches to manipulate molecular targets within specific brain region(s). We also evaluate co-morbid neuropsychiatric conditions including anxiety and depression as part of a comprehensive behavioral neuroscience strategy. The lab culture is collaborative and dynamic, innovative, and team-based. We are looking for colleagues who share an interest in understanding how alcohol hijacks reward pathways to produce addiction.


Our research focuses on understanding the molecular and cellular mechanisms of leukocyte (white blood cell) trafficking and homing in vascular inflammation and immune responses. We are interested in the glycobiology of the Selectin leukocyte adhesion molecules and their ligands, and understanding the roles for these glycoproteins in the pathogenesis of inflammatory/immune cardiovascular diseases such as atherosclerosis and vasculitis. We are also interested in the mechanisms whereby the selectins and their ligands link the inflammatory response and coagulation cascade and thereby modulate thrombosis and hemostasis.


Hopfinger, Joseph
Website | Email
Publications
PHD PROGRAM
Neurobiology
RESEARCH INTEREST
Behavior, Neurobiology

Research in my laboratory investigates human cognition. We use behavioral measures and scalp-recorded event-related brain potentials (ERPs) to gain a better understanding of the rapid neural dynamics underlying cognitive processes, such as the interactions between attentional capture, sustained attention, and distraction.  We also use fMRI to investigate the neural architecture supporting voluntary attention, as well as social cognitive processes.  A new direction of our research is using these methods to investigate changes in neural connectivity that may be associated with cognitive “brain training.” Finally, in collaborative projects, we also investigate social cognitive processing in psychiatric populations, language comprehension in healthy individuals, and dysfunctional attentional control in adults at risk for alcoholism.


Hursting, Stephen D
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Publications
PHD PROGRAM
Nutrition

Dr. Hursting’s lab focuses on the molecular and metabolic mechanisms underlying nutrition and  cancer associations, particularly the impact of obesity and energy balance modulation (eg, calorie restriction, exercise) on cancer development or responses to chemotherapy. Primarily using genetically engineered mouse models of pancreatic, colon and breast cancer, Dr. Hursting has identified the IGF-1/Akt/mTOR and NF-kB signaling pathways as key targets for breaking the obesity- cancer link.  He has also established in several preclinical models of pancreatic and breast cancer that obesity impacts the response to various forms of chemotherapy.  In addition, the Hursting lab is involved in several translational research collaborations linking mouse model studies with clinical trials, and his group has expertise in measuring metabolic hormones, growth factors, inflammatory cytokines and chemokines in serum and tissue from rodents and humans.


The lab focus is to understand the mechanism of gene-environment interactions by examining the genetic basis of epigenetic response to nutrition and environmental toxicants. The long-term goal is to identify and characterize genetic (naturally occurring and induced) and environmental (toxicant and nutritional) causes of disruption of DNA methylation patterns during development and to determine their role in disease. The primary focus is on DNA methylation patterns during germ cell and early embryonic development during critical windows of epigenetic reprogramming.


My research focus pertains to vascular remodeling as it relates to the pathogenesis and progression of thoracic aortic aneurysms. Using murine and porcine models, as well as human aneurysm tissue samples, we study proteinase and signaling biology with a view towards defining novel modalities targets for diagnosis, tracking, risk stratification and non-surgical treatment of this devastating disease.


James, Lindsey Ingerman
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Publications

We are interested in modulating the activity of chromatin reader proteins with small-molecule ligands, specifically potent and selective chemical probes, in order to open new avenues of research in the field of epigenetics. Our work has pioneered the biochemical assays and medicinal chemistry strategies for high quality probe development for methyl-lysine (Kme) reader proteins, as well as the means by which to evaluate probe selectivity, mechanism of action, and cellular activity. Using a variety of approaches, we utilize such chemical tools to improve our understanding of their molecular targets and the broader biological consequences of modulating these targets in cells. We are also interested in developing novel methods and screening platforms to discover hit compounds to accelerate Kme reader probe discovery, such as affinity-based combinatorial strategies, as well as innovative techniques utilizing our developed antagonists to more fully understand the dynamic nature of chromatin regulation.


The Jarstfer lab uses an interdisciplinary approach to solve biological problems that are germane to human health.   Currently we are investigating the structure of the enzyme telomerase, we are developing small-molecules that target the telomere for drug discovery and chemical biology purposes, and we are investigating the signals that communicate the telomere state to the cell in order to control cellular immortality. We are also engaged in a drug/chemical tool discovery project to identify small molecules that control complex social behavior in mammals.  Techniques include standard molecular biology and biochemistry of DNA, RNA, and proteins, occasional organic synthesis, and high throughput screening.


Research in my lab focuses on the mechanisms by which exposure to air pollutants alters respiratory immune responses and modifies susceptibility to and the severity of respiratory virus infections. Specifically, we are examining the effects of air pollutants such as ozone, woodsmoke and tobacco product exposures on host defense responses and influenza virus infections, using several in vitro models of the respiratory epithelium. In collaboration with physician scientists, we are also translating these studies into humans in vivo.


My research interests and diagnostic responsibilities center around nephropathology and immunopathology. My laboratory carries out basic, translational and clinicopathologic research on kidney diseases. I am most interested in pathogenic mechanisms and pathologic manifestations of glomerular diseases and vasculitis. A major current research focus is on elucidating the pathogenesis of vascular inflammation caused by anti-neutrophil cytoplasmic autoantibodies (ANCA).


Dr Jiang’s primary research interests lie in statistical modeling, method development and data analysis in genetics and genomics. His current research is focused on developing statistical methods and computational algorithms to better utilize and analyze different types of next-generation sequencing data under various setting, with application to data from large-scale cohort studies of human health and disease. Special focus is on single-cell transcriptomics, single-cell epigenomics, cancer genomics, tumor phylogeny, data normalization, and copy number variation detection.


Research in the Jian Jin lab focuses on the following two main areas: (1) discovering chemical probes for histone methyltransferases (HMTs), a class of more than 50 epigenetic writers that play a critical role in diverse biological processes including chromatin compaction, gene expression, transcriptional regulation, and cell differentiation; and (2) creating functionally selective ligands of G protein-coupled receptors (GPCRs) for treating various central nervous system (CNS) disorders.


The Jones lab is interested in heterotrimeric G protein-coupled signaling and uses genetic model systems to dissect signaling networks.  The G-protein complex serves as the nexus between cell surface receptors and various downstream enzymes that ultimately alter cell behavior. Metazoans have a hopelessly complex repertoire of G-protein complexes and cell surface receptors so we turned to the reference plant, Arabidopsis thaliana, and the yeast, Saccharomyces cerevisiae, as our models because these two organisms have only two potential G protein complexes and few cell surface receptors.  Their simplicity and the ability to genetically manipulate genes in these organisms make them powerful tools.  We use a variety of cell biology approaches, sophisticated imaging techniques, 3-D protein structure analyses, forward and reverse genetic approaches, and biochemistries.


The goal of my research is to identify, clone, and characterize the evolution of genes underlying natural adaptations in order to determine the types of genes involved, how many and what types of genetic changes occurred, and the evolutionary history of these changes. Specific areas of research include: 1) Genetic analyses of adaptations and interspecific differences in Drosophila, 2) Molecular evolution and population genetics of new genes and 3) Evolutionary analysis of QTL and genomic data.


Despite recent success in reducing malaria transmission, the estimated annual numbers of malaria infections (~225 million) and deaths (~781,000) remain high. Despite this immense burden, our understanding of the genetic diversity of malaria and the factors that promote this diversity is limited.  This diversity among plasmodial parasites has a critical impact on many factors involved in the control of infections, including: 1) development of drug resistance, 2) development of naturally acquired immunity, and 3) vaccine design.  My laboratory’s primary interests are: 1) describing the genetic diversity of P. falciparum using molecular biological and next generation sequencing tools, and 2) using these data to understand the evolutionary and ecological factors that drive this diversity, promote the emergence of drug resistance and affect our ability to effectively develop immunity.


Kabanov, Alexander (Sasha)
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Publications

In our lab we develop novel polymer based drug delivery systems and nanomedicines incorporating small molecules, DNA and polyptides to treat cancer, neurodegenerative and other CNS-related disorders.


Our lab is focused on the development of HIV-1 vectors for gene therapy of genetic disease.  In addition, we are using the vector system to study HIV-1 biology.  We are also interested in utilizing the HIV-1 vector system for functional genomics.


Kakoki, Masao
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Publications
RESEARCH INTEREST
Genetics, Pathology

My research aims at prevention and treatment of cardiovascular diseases and focuses on the identification of genes that confer susceptibility or resistance to the diseases with the use of genetically engineered mice. In collaboration with Dr.Oliver Smithies, I very recently developed a new method for altering gene expression by modifying 3’ untranslated regions in mice which enables fine-tuned modification of gene expression. I am now analyzing the phenotypes of several mouse models generated with this method.


Emotional behavior is regulated by a host of chemicals, including neurotransmitters and neuromodulators, acting on specific circuits within the brain. There is strong evidence for the existence of both endogenous stress and anti-stress systems. Chronic exposure to drugs of abuse and stress are hypothesized to modulate the relative balance of activity of these systems within key circuitry in the brain leading to dysregulated emotional behavior. One of the primary focuses of the Kash lab is to understand how chronic drugs of abuse and stress alter neuronal function, focusing on these stress and anti-stress systems in brain circuitry important for anxiety-like behavior. In particular, we are interested in defining alterations in synaptic function, modulation and plasticity using a combination of whole-cell patch-clamp physiology, biochemistry and mouse models.  Current projects are focused on the role of a unique population of dopamine neurons in alcoholism and anxiety.


Kato, Hiroyuki
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Publications
PHD PROGRAM
Neurobiology
RESEARCH INTEREST
Behavior, Neurobiology, Physiology

Our primary goal is to identify how our brain processes sound inputs to detect complex patterns, such as our language. Using mouse auditory cortex as a model system, we combine multiple cutting-edge techniques (e.g. in vivo whole-cell recording, two-photon calcium imaging, and optogenetics) in behaving animals to dissect the circuits that connect vocal inputs to behavioral outputs. Findings in the simple mouse cortex should provide a first step towards the ultimate understanding of the complex human brain circuits that enable verbal communication, and how they fail in psychiatric disorders.


Topic 1  We seek genomic targets for carcinogenesis among segments of DNA replicated in early S phase when cells are most susceptible to carcinogens.  We are mapping genomic sites replicated during early S phase, identifying origins of replication activated in this interval, and characterizing temporal sequencing of replication from these origins.  Topic 2  We are reconstructing differentiated and functional human endometrial tissue from epithelial and stromal cells interacting in culture.  We use these co-cultures to study development of endometrial cancer.


While both genes and environment are thought to influence human health, most investigations of complex disease only examine one of these risk factors in isolation.  Accounting for both types of risk factors and their complex interactions allows for a more holistic view of complex disease causation.  The Kelada lab is focused on the identification and characterization of these gene-environment interactions in airway diseases, particularly asthma, a disorder of major public health importance.   /  / Additionally, to gain insight into how the airway responds to relevant exposures (e.g., allergens or pathogens), we study gene expression in the lung (particularly airway epithelia). Our goal is identify the genetic determinants of gene expression by measuring gene expression across many individuals (genotypes). / This “systems genetics” approach allows us to identify master regulators of gene expression that may underlie disease susceptibility or represent novel therapeutic targets. /


The upper airways serve to clean inspired air from physical, chemical and pathological detritus that might damage the delicate peripheral airways where oxygen exchange is achieved. It is the heart of a powerful two tiered  innate immune system based upon a  layer of mucus that captures the incoming material that is moved over a bed of cilia. The system is called the muco-ciliary escalator.
Failure of this complex protective system is associated with a wide variety of diseases such as cancer and chronic inflammatory diseases. Biomolecules in mucus are split into two distinct groups, the first group being of globular type proteins between 6 kDa to 200 kDa and the second being of mucins which are large, space-filling glycoconjugates of 200 kDa to 100 MDa, with most of this mass being of carbohydrate in origin. Besides these biomolecules, mucus also contains secreted vesicles (exosomes) with innate immune properties. In chronic inflammatory lung diseases like cystic fibrosis (CF), chronic bronchitis (COPD) and asthma, mucus quantity and quality is altered and it is not efficiently removed from the lungs, causing airway obstruction, impaired gas exchange, bacterial colonization & infection and damage to lung tissue. The long term goal of our laboratory is to understand how this innate immune barrier is dynamically organized around the protective macromolecules under normal and pathological conditions. Currently, research in the Kesimer laboratory is focused on three main fundamentally important areas: 1- How mucins and globular proteins are organized within the airway mucosal barrier and how they are altered in disease pathogenesis, 2- How mucins are processed to mature after granular release for optimal function and how this progression is altered in chronic lung diseases, CF in particular, and 3- The role of extracellular vesicles in the airway mucosal barrier. Our laboratory is established with a wide range of state of the art biochemical, biophysical and proteomics methods including UPLC-Orbitrap mass spectrometry, atomic force microscopy, dynamic and static light scattering, and a variety of surface biophysics tools including QCM-D.


Hormones influence virtually every aspect of plant growth and development. My lab is examining the molecular mechanisms controlling the biosynthesis and signal transduction of the phytohormones cytokinin and ethylene, and the roles that these hormones play in various aspects of development. We employ genetic, molecular, biochemical, and genomic approaches using the model species Arabidopsis to elucidate these pathways.


Kier, William
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Publications
PHD PROGRAM
Biology

I am interested in the comparative biomechanics of marine invertebrates.  In particular, I study the functional morphology of musculoskeletal systems, the structure, function, development and evolution of muscle, and invertebrate zoology, with particular emphasis on the biology of cephalopod molluscs (octopus and squid).  My research is conducted at a variety of levels and integrates the range from the behavior of the entire animal to the ultrastructure and biochemistry of its tissues.


Our research explores the role of hypoxia-inducible factor (HIF) in tumorigenesis. HIF is a transcription factor that plays a key role in oxygen sensing, the adaptation to hypoxia and the tumor microenvironment. It is expressed in the majority of solid tumors and correlates with poor clinical outcome. Therefore, HIF is a likely promoter of solid tumor growth and angiogenesis.  Our lab uses mouse models to ask if and how HIF cooperates with other oncogenic events in cancer.  We are currently investigating HIF’s role in the upregulation of circulating tumor cells and circulating endothelial cells.


Kleeberger, Steven
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Publications
PHD PROGRAM
Toxicology

Genetic determinants of environmental lung diseases.


Ko’s laboratory has focused on bone regeneration using biomaterials and biomechanical approaches. The on-going project is to develop a new synthetic process for biomimetic bone nanocomposites. The new biomaterial and its scaffolds are under development for stem cell-mediated bone regeneration. Biomechanical principles that regulate mineral crystallization are incorporated with the biomaterial approach to translate research outcomes to clinical usage (e.g., immediately loaded dental implants). My lab is also interested in understanding reverse engineering principles of bio-mienralization.


Our research focuses on understanding mechanisms of cardiovascular and metabolic health effects of inhaled air pollutants. Specific emphasis is given to susceptibility variations due to underlying cardiovascular disease, obesity, and diabetes. The roles of genetic versus physiological factors are examined. We use molecular and high throughput genomics, and proteomics techniques to establish a link with disease phenotype and physiological alterations. State-of-the-art EPA inhalation facilities are used for air pollution exposures in animal models with or without genetic predisposition. The role of environment in disease burden is the focus.


Dr. Krupenko’s research is focused on the role of folate metabolism in cellular homeostasis and cancer disease. He is especially interested in the function of a major folate enzyme and a putative tumor suppressor ALDH1L1 as metabolic regulator and a guardian of non-malignant phenotype. At present he studies function of this enzyme and related proteins using mouse knockout models. Recently his research team has also demonstrated that dietary folate regulates cancer metastasis. He now pursues studies of specific signaling pathways involved in metastatic response to dietary folate status.


My laboratory is interested in the role of folate and related metabolic pathways in methyl group metabolism, and their involvement in pathogenesis and etiology of diseases. We have recently discovered a novel function of a folate-binding methyltransferase GNMT in the regulation of cellular proliferation, and now study the genetic variations in GNMT and their effects on new function. Our lab is also interested in the cross talk between folate metabolism and sphingolipid pathways as a mediator of folate stress with the goal of exploiting this connection to improve human health.


We use a combination of experimental and computational methods to redesign protein-protein interactions.  The potential applications for this technology include enhancing protein therapeutic and creating new tools to study signaling pathways.


The Laederach Lab is interested in better understanding the relationship between RNA structure and folding and human disease. We use a combination of computational and experimental approaches to study the process of RNA folding and in the cells. In particular, we develop novel approaches to analyze and interpret chemical and enzymatic mapping data on a genomic scale. We aim to fundamentally understand the role of RNA structure in controlling post-transcriptional regulatory mechanisms, and to interpret structure as a secondary layer of information (http://www.nature.com/nature/journal/v505/n7485/full/505621a.html).  We are particularly interested in how human genetic variation affects RNA regulatory structure. We investigate the relationship between disease-associated Single Nucleotide Polymorphisms occurring in Human UTRs and their effect on RNA structure to determine if they form a RiboSNitch.


Our dynamic group are broadly involve in three topics: (i) prevention of infectious diseases by harnessing interactions between secreted antibodies and mucus, (ii) immune response to biomaterials, and (iii) targeted delivery of nanomedicine.  Our group was the first to discover that secreted antibodies can interact with mucins to trap pathogens in mucus.  We are now harnessing this approach to engineer improved passive and active immuniation (i.e. vaccines) at mucosal surfaces, as well as understand their interplay with the mucosal microbiome.  We are also studying the adaptive immune response to polymers, including anti-PEG antibodies, and how it might impact the efficacy of PEGylated therapeutics.  Lastly, we are engineering fusion proteins that can guide targeted delivery of nanomedicine to heterogenous tumors and enable personalized medicine.


Dr. Lange’s primary research interests are in the development and application of statistical methods to genetic data. His methodological work has focused on developing techniques for haplotype-based association analyses, linkage analysis, and genetic power analyses.


Living cells have been referred to as the test tubes of the 21st century. New bioactive reagents developed in our lab are designed to function in cells and living organisms. We have prepared enzyme inhibitors, sensors of biochemical pathways, chemically-altered proteins, and activators of gene expression. In addition, many of these agents possess the unique attribute of remaining under our control even after they enter the biological system. In particular, our compounds are designed to be inert until activated by light, thereby allowing us to control their activity at any point in time.


We use molecular virology approaches and mouse models of infection to understand innate immune mechanisms that control arbovirus pathogenesis (e.g. West Nile, Zika, and La Crosse viruses). Bat flaviviruses have unusual vector/host relationships; understanding the viral and host factors that determine flavivirus host range is important for recognizing potential emerging infections. We are studying the antiviral effects of interferon lambda (IFN-λ) at barrier surfaces, including the blood-brain barrier and the skin. We also use mouse models of atopic dermatitis and herpes simplex virus infection to understand the effects of IFN- λ in the skin.


Dr. Edward (Ed) LeCluyse is currently a Senior Research Investigator in the Institute for Chemical Safety Sciences at The Hamner Institutes of Health Sciences.  Dr. LeCluyse leads a program initiative to identify and develop novel in vitro hepatic model systems to examine cellular responses to drugs and environmental chemicals that target known toxicity pathways. The focus of his research efforts has been to create more organotypic, physiologically-relevant in vitro models that integrate the architectural, cellular and hemodynamic complexities of the liver in vivo.


We study protein structure and dynamics as they relate to protein function and energetics. We are currently using NMR spectroscopy (e.g. spin relaxation), computation, and a variety of other biophysical techniques to gain a deeper understanding of proteins at atomic level resolution.  Of specific interest is the general phenomenon of long-range communication within protein structures, such as observed in allostery and conformational change.  A. Lee is a member of the Molecular & Cellular Biophysics Training Program.


Life is animate and three-dimensional.  Our lab develops tools to better understand living specimens at single molecule, cellular, and tissue level length scales.  Our current efforts comprise three synergistic research areas: 1) development and application of novel fluorescent imaging modalities including: super resolution, light sheet, and adaptive optical microscopy 2) investigation of how mechanical forces and cytoskeletal dynamics drive cancer cell migration through complex three-dimensional environments, and 3) generation of microfabricated platforms to precisely control the cellular microenvironment for tissue engineering and drug screening.


Our research focuses on the discovery and design of new gene-encoded bioactive small molecules from bacteria.  We are interested in understanding enzymes involved in their biosynthesis, their therapeutic mechanisms of action, and implications in health and diseases, in particular with respect to the human microbiome.  This work is driven by intensive development of new metabolomics and genomics technologies.  We subsequently manipulate and engineer these biosynthetic pathways to make new and improved molecules as potential therapeutics such as antibiotics.


The Yun Li group develops statistical methods and computational tools for modern genetic, genomic, and epigenomic data. We do both method development and real data applications. The actual projects in the lab vary from year to year because I am motivated by real data problems, and genomics is arguably (few people argue with me though) THE most fascinating field with new types and huge amount of data generated at a pace more than what we can currently deal with. For current projects, please see: http://www.unc.edu/~yunmli/BCBrotationAds/


We use high-throughput DNA sequencing, microarrays, and other technologies to study how and where proteins interact with the genome, and how these interactions affect the biology of living cells. We use three systems: yeast, C. elegans and human. Our C. elegans studies focus on developmental processes, and we use human cell lines and clinical samples to study diseases like cancer and diabetes. All of our projects focus on chromatin and DNA-binding proteins.


Congenital heart diseases are one of the most common birth defects in humans, and these arise from developmental defects during embryogenesis.  Many of these diseases have a genetic component, but they might also be affected by environmental factors such as mechanical forces. The Liu Lab combines genetics, molecular and cell biology to study cardiac development and function, focusing on the molecular mechanisms that link mechanical forces and genetic factors to the morphogenesis of the heart.  Our studies using zebrafish as a model system serve as the basic foundation to address the key questions in cardiac development and function, and could provide novel therapeutic interventions for cardiac diseases.


If you are interested in developing new biochemical/molecular techniques/tools to advance our understanding of biology, and if you are interested in signal transduction pathway analyses and identification of cancer biomarkers, our research group may help you to achieve your goals, as we have the same dreams. We are especially interested in deciphering the molecular mechanisms underlying aberrant signaling events that contribute to tumorigenesis, mediated through protein modifications and protein-protein interactions. Understanding these events may lead to identification of novel drug targets and provide new treatment strategies to combat human cancer.


The research interests of the Liu Lab are in functional proteomics and biopharmaceuticals. Currently we are working on the following projects:  (1). Using systems biology approaches to decipher the signaling pathways mediated by disease-related proteases such as caspases and granzymes and by post-translationally modified histones. We address these problems by performing functional protein selections using mRNA-displayed proteome libraries from human, mouse, Drosophila, and C. elegans. (2). Developing novel protein therapeutics and nucleic acid therapeutics that can be used in tumor diagnosis, treatment, and nanomedicine. We use various amplification-based molecular evolution approaches such as mRNA-display and in vivo SELEX to develop novel single domain antibody mimics on the basis of very stable protein domains or to generate aptamers on the basis of nuclease-resistant nucleic acids, that bind to important biomarkers on the surface of cancer cells. We further conjugate these biomarker-binding affinity reagents to small molecule drugs or nanoparticles for targeted delivery of therapeutic agents. (3). Identifying the protein targets of drugs or drug candidates whose action mechanisms are unknown. We combine molecular proteomic and chemical biology approaches to identify the protein targets of drugs whose target-binding affinities are modest.


Statistical machine learning and data mining, nonparametric statistics and functional estimation, bioinformatics, design and analysis of experiments

 


Biochemistry, cell biology, and immunology of skin, immunopathogenesis of autoimmune and inflammatory skin blistering diseases.


The overall goal of our research is to develop an enzyme-based approach to synthesize heparin- and heparan sulfate-like therapeutics.  The lab is currently focusing on improving the anticoagulant efficacy of heparin drug as well as synthesizing heparin-like compounds that inhibit herpes simplex virus infections.  We are also interested in using protein and metabolic engineering approaches for preparing polysaccharides with unique biological functions.


Lockett, Ryen Matthew
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Publications
PHD PROGRAM
Chemistry

Research in the Lockett group focuses on the development of analytical model systems to: i) chemically modify the surface of thin films, and study chemical and biochemical reactions occurring on those surfaces; ii) study drug metabolism in an environment that closely mimics the human liver; iii) measure tumor invasion in an environment that closely mimics human tissue. /  / While these problems require techniques found in analytical chemistry, biochemistry, molecular biology, bioengineering, and surface science we are particularly interested in the technologies that allow us to quantitatively measure reactions and analytes.


The Loeser lab uses a combination of in vitro studies in articular chondrocytes and in vivo studies in mice to examine molecular mechanisms of joint tissue destruction in aging and osteoarthritis. A major focus of this work is examining how reactive oxygen species regulate cell signaling through oxidation of Cys residues in specific kinases and phosphatases. Pathways of interest include integrin mediated signaling that stimulates matrix metalloproteinase (MMP) expression and IGF-I signaling that stimulates matrix production. Oxidative stress disrupts the balance in the activity of these pathways to favor matrix destruction over repair contributing to the development of osteoarthritis.


Lohman, Kenneth
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Publications
PHD PROGRAM
Biology
RESEARCH INTEREST
Neurobiology

Our lab group is interested in the behavior, sensory ecology, neuroethology, and conservation biology of animals, particularly those that live in the ocean. Research focuses include: (1) physiology and ecology of animals that migrate long distances; (2) navigational mechanisms of sea turtles, spiny lobsters, monarch butterflies, and salmon; (3) neuroethology and behavioral physiology of invertebrate animals; (4) use of the Earth’s magnetic field in animal navigation; (5) technoethology (the use of novel computer and electronic technology to study behavior).


Cytoskeletal-associated proteins are critical for the maintenance of cellular homeostasis, and their involvement in cancer and in numerous neurodegenerative, neurodevelopmental, psychiatric, heart, muscular, and metabolic disorders underscores their functional relevance.

Our lab investigates the contribution of the cytoskeleton to key physiological processes and the mechanistic basis of cytoskeleton-associated disorders. Our goal is to understand the roles of cytoskeletal proteins in the regulation of cellular dynamics and bioenergetics in metabolically active tissues as well as their involvement in brain development and connectivity. Our initial efforts focus on the ankyrin and spectrin families of cytoskeletal-associated proteins, which deficits have direct implications in the regulation of cell migration, in metabolic disorders such as obesity and diabetes, and may also underlie neurological diseases, including spinocerebellar ataxias, autism and West syndrome.

We combine human genetics, cellular and biochemistry approaches with Omics technologies and high resolution imaging-based assays in primary cells and in animal models of development and human disease.


Molecular, cellular and in vivo approaches in intestine to define mechanisms by which hormones and growth factors regulate normal growth and cancer. Uses model cell lines, mutant mice, mouse models of disease, translational approaches to growth factor action and signal transduction, gut immune interactions in obesity.


Lysle, Donald
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Publications
PHD PROGRAM
Neurobiology
RESEARCH INTEREST
Immunology, Neurobiology

Psychoneuroimmunology; the effects of conditioning on lymphocyte reactivity


MacDonald, Jeffrey
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Publications
PHD PROGRAM
Toxicology

Dr. Macdonald is the Founder and Scientific Director of the new Metabolomic Facility and Co-Scientific Director of the joint UNC/NCSU/NOAA Marine MRI facility at Pivers Island near Beaufort NC. Dr. Macdonald’s research goal is to combine metabolomics and tissue engineering and apply these tools to quantitative biosystem analysis.


My research goals are to identify the mechanisms by which environmental factors regulate smooth muscle cell phenotype and to define the transcriptional pathways that regulate SMC-specific gene expression.


The major focus of Mackman lab is the procoagulant protein tissue factor. This is the primary cellular initiator of blood coagulation. We study its role in hemostasis, thrombosis, inflammation, ischemia-reperfusion injury and tumor growth.  LPS induction of the tissue factor gene in human monocytic cells and endothelial cells is mediated by various transcription factors, such as AP-1, NF-ĸB and Egr-1. More recently, we found that the phosphatidylinositol-3-kinase protein kinase B intracellular signaling pathway suppresses LPS activation of monocytes and endothelial cells.  We found that inhibition of either tissue factor or the downstream coagulation protease thrombin reduced infarct size in a rabbit model of cardiac ischemia-reperfusion injury. We showed that the tissue factor-thrombin pathway increased inflammation during myocardial ischemia-reperfusion injury by inducing chemokine expression and enhancing the recruitment of neutrophils. We have generated a number of mouse models expressing different levels of both mouse and human tissue factor. These mice have been used to provide new insights into the role of tissue factor in hemostasis and thrombosis. In 2007, we developed a new assay to measure levels of microparticle tissue factor in plasma. We found that elevated levels of microparticle tissue factor are associated with venous thromboembolism in cancer patients.


The major focus of Mackman lab is the procoagulant protein tissue factor. This is the primary cellular initiator of blood coagulation. We study its role in hemostasis, thrombosis, inflammation, ischemia-reperfusion injury and tumor growth. LPS induction of the tissue factor gene in human monocytic cells and endothelial cells is mediated by various transcription factors, such as AP-1, NF-ĸB and Egr-1. More recently, we found that the phosphatidylinositol-3-kinase protein kinase B intracellular signaling pathway suppresses LPS activation of monocytes and endothelial cells. We found that inhibition of either tissue factor or the downstream coagulation protease thrombin reduced infarct size in a rabbit model of cardiac ischemia-reperfusion injury. We showed that the tissue factor-thrombin pathway increased inflammation during myocardial ischemia-reperfusion injury by inducing chemokine expression and enhancing the recruitment of neutrophils. We have generated a number of mouse models expressing different levels of both mouse and human tissue factor. These mice have been used to provide new insights into the role of tissue factor in hemostasis and thrombosis. In 2007, we developed a new assay to measure levels of microparticle tissue factor in plasma. We found that elevated levels of microparticle tissue factor are associated with venous thromboembolism in cancer patients.


Madden, Michael C.
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Publications
PHD PROGRAM
Toxicology

Exposure to ambient air particulate matter  has been associated with increased human deaths and cardiopulmonary morbidity, such as lung infections and increased asthma symptoms.  I am investigating some types of PM and associated gases  that may be associated with those health effects so  to better regulate or manage the sources of the airborne particles which are identified as playing a role in the adverse health outcomes. I am currently focusing on the effects of diesel exhaust using a variety of approaches ranging from exposing cultured human lung and vascular cells to the exhaust, to studying responses of humans exposed out in traffic.  I am currently designing and implementing testing strategies to assess the toxicity of the future types of vehicular emissions. Additionally some of my research effort attempts to identify what populations are more sensitive to the effects of air pollutants, and the genetic, diet, and environmental reasons behind the increased sensitivity.


My research program is centered on understanding fundamental aspects of cell division. During cell division, complex DNA-protein interactions transform diffuse interphase chromatin into discrete mitotic chromosomes, condensing them several thousand fold to facilitate spatial segregation of sister chromatids. Concomitantly, kinetochores form specifically at centromere regions of chromosomes and regulate force-producing interactions with microtubules. While these processes are absolutely required for genomic stability, the in vivo mechanisms of chromosome and kinetochore assembly remain unsolved problems in biology. I investigate 1) the spatiotemporal regulation of mitotic chromosome assembly, and 2) the molecular basis of centromere specification. To do so, I will combine biochemical approaches with high-resolution light microscopy of live cells, whole organisms, and in vitro systems.


My research philosophy is summed up by a quote from Nobelist Albert Szent-Gyorgyi: “Discovery is to see what everybody has seen and to think what nobody has thought.” My lab studies the molecular and physical mechanisms of cell shape change during cytokinesis and tissue biogenesis during development. Specifically, we are defining how cells ensure proper alignment and sliding of cytoskeletal filaments, and determining the shape of the cell throughout division. To do so, we combine developmental biology, cell biology, biochemistry, and quantitative image analysis.


Our research is focused on the genetics and molecular pathology of complex multi-factorial conditions in humans – obesity, diabetes, hypercholesterolemia, insulin resistance, and hypertension.  These conditions underlie cardiovascular diseases, including atherosclerosis, the major cause of death and disabilities in North America. Our approach consists of experiments with mice carrying modifications in various genes important for the maintenance of vascular function, antioxidant defense, and metabolism.  We dissect how gene-gene and gene-environment interaction influences the pathogenesis of these common human conditions and their complications.


The primary focus of my research is to understand the genetic mechanisms underlying stem cell maintenance and differentiation with the goal of translating this information into therapeutic strategies. Using a Sox9EGFP mouse model and FACSorting we are able to specifically enrich for single multipotent intestinal epithelial stem cells that are able to generate mini-guts in a culture system. Our studies are now focused on manipulating, in vitro, the genetics of stem cell behavior through viral gene therapeutics and pharmacologic agents. Additionally, we are developing stem cell transplantation and tissue engineering strategies as therapies for inborn genetic disorders as well as damage and disease of the intestine. Using novel animal models and tissue microarrays from human colon cancers, we are investigating the role of Sox-factors in colorectal cancer.


The Magnuson Lab works in three areas – (i) Novel approaches to allelic series of genomic modifications in mammals, (ii)Mammalian polycomb-group complexes and development, (iii) Mammalian Swi/Snf chromatin remodeling complexes


An overwhelming number of burn patients die from wound infection and sepsis. Our laboratory, along with Dr Bruce Cairns, investigates translational immune mechanisms within mouse models and burn patients. Focuses in the lab include 1) investigation of innate molecule control of both the innate and adaptive immune systems after burn injury, 2) role of innate signaling to Damage Associated Molecular Patterns in Immune Dysfunction after burn / inhalational injury 3) using NRF2/KEAP1-Targeted Therapy to Prevent Pneumonitis and Immune Dysfunction After Radiation or Combined Burn-Radiation Injury and 4) Investigating sex-specific disparities in Immune Dysfunction


The overall goal of my lab is to understand how alterations in signal transduction pathways contribute to human cancer.  To that end, a systems level approach is employed wherein functional genomics, mass spectrometry-based proteomics, gene expression and mutation data are integrated.  The resulting cancer-annotated physical/functional map of a signal transduction pathway provides us with a powerful tool for mechanistic discovery in cancer biology.  We are currently working in lymphoma and lung cancer models, with a focus on the Wnt/b-catenin and Keap1/Nrf2 pathways.


Physiology and pharmacology of the basal ganglia; neurobiology of motivation and reward; substance abuse neurobiology; and neurobehavioral teratology. My laboratory studies the function of neural circuitry involved in the perception of reward and the reinforcement of motivated behaviors in several mouse models of neurodevelopmental disorders, including early developmental exposure to drugs of abuse, such as alcohol or cocaine; and genetic models relevant to the study of autism, such as inactivation of the Fmr1 (Fragile-X Mental Retardation) or MeCP2 (Methyl-CpG Binding Protein) genes.  My laboratory employs techniques in behavioral pharmacology, including intracranial self-stimulation (ICSS); in vitro patch-clamp electrophysiology in acute brain slices; and immunohistochemistry with unbiased stereological microscopy.


My research focuses on molecular mechanisms of mammalian nervous system development. We investigate mechanisms by which developing neurons migrate to the neocortex and form connections.


We are interested in the cellular and network mechanisms of sensory information processing in the central nervous system, with an emphasis on the neural substrates for hearing. We study functional network organization, synaptic function, the roles of ion channels and cellular excitability, and short and long-term synaptic plasticity, in the auditory brainstem and auditory cortex.  Experimentally, we use patch clamp methods in brain slices, optogenetics and laser scanning photostimulation, multiphoton imaging, and computational neuroscience (modeling), in normal and transgenic mouse models. The lab also has collaborative projects related to schizophrenia (prefrontal cortex; Dr. Patricia Maness, UNC) and connectomics (cochlear nucleus and MNTB; Dr. George Spirou, WVU).


We are a biological oceanography lab that performs inquiry-based science by combining physiological and molecular approaches in laboratory isolates and natural communities to investigate how marine microorganisms are affected by their environment and in turn, influence ocean biogeochemistry and ecosystem dynamics. Particular interests include studying trace metals, such as iron, that are essential for the nutrition of phytoplankton and predicting the effects of future climate changes on phytoplankton distribution and abundance.  We implement the use of environmental genomic approaches (e.g. RNA-seq) to ascertain the ways in which marine microbes have adapted and acclimate to varying environmental conditions.


The overall goal of our laboratory is to obtain new insights into the host-virus interaction, particularly in HIV infection, and translate discoveries in molecular biology and virology to the clinic to aid in the treatment of HIV infection. A subpopulation of HIV-infected lymphocytes is able to avoid viral or immune cytolysis and return to the resting state. Current work focuses on the molecular mechanisms that control the latent reservoir of HIV infection within resting T cells. We have found that cellular transcription factors widely distributed in lymphocytes can remodel chromatin and maintain quiescence of the HIV genome in resting CD4+ lymphocytes. These studies give insight into the basic molecular mechanisms of eukaryotic gene expression, as well as new therapeutic approaches for HIV infection.


The focus of the work in the Martinez lab is to examine the non-canonical roles for the autophagy machinery during inflammation. Our recent work about LC3-associated phagocytosis (LAP) higlights the importance of this non-canonical autophagic process in maintaining tolerance and preventing unwanted autoinflammatory pathologies.


We are interested in the mechanisms by which histone protein synthesis is coupled to DNA replication, both in mammalian cell cycle and during early embryogenesis in Drosophila, Xenopus and sea urchins.


Research in our laboratory is focused on RNA. We aim to understand how ribonucleoprotein particles (snRNPs, mRNPs, etc.) are transcribed, packaged and transported to their final destinations in the cell.  We are also interested in the genetic and epigenetic forces that direct formation of microscopically visible subcellular structures (e.g. nuclear bodies). We use a combination of approaches, including Drosophila genetics, molecular cell biology, biochemistry, digital imaging microscopy and genome-wide analyses. Projects in the lab are focused on two areas:  models of a neurogenetic disease called Spinal Muscular Atrophy (SMA) and the functional analysis of post-translational modifications of chromatin and RNA-binding proteins important in cancer and other diseases.


Research in our laboratory is focused on the enzymatic mechanisms and biological roles of DNA helicases which convert duplex DNA to ssDNA for use as a template in DNA replication and repair or as a substrate in recombination.  Defects in genes encoding DNA helicases have been linked to genomic instability leading to a variety of progeriod disorders and human cancers. Our long-range goal is to understand the mechanism of action of helicases and to define their roles in DNA metabolism. The lab also has an interest in the process of DNA transfer by bacterial conjugation – the unidirectional and horizontal transmission of genetic information from one cell to another. Conjugative DNA transfer plays a role in increasing genetic diversity in addition to propagating the spread of antibiotic resistance and microbial virulence factors. Our long-range goal is to define the function and regulation of the relaxosome, and each protein in this nucleoprotein complex, in conjugative DNA transfer.


Our laboratory is interested in innate immune responses during injury to the central nervous system and during inflammation during microbial infections.  Our laboratory has a special interest in autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus.  We also are pursuing drug discovery projects targeting receptors that may modulate demyelinating disease and immune responses.  We use molecular, cellular and biochemical approaches both in vitro and in vivo to identify the function of key mediators during pathogenesis.


Dr. McCullough’s lab focuses around the role of the epigenetic elements as both a molecular mechanism mediating the effects of toxic exposures and as a biomarker for predicting susceptible populations and identifying factors that can be used to mitigate adverse health outcomes.  The lab employs a translational research approach to toxicology with an emphasis on molecular biology that uses both advanced in vitro primary cell models and in vivo clinical controlled human exposure studies.


McElligott, Zoe
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Publications
PHD PROGRAM
Neurobiology

Research in the McElligott lab focuses on the circuits and plasticity that underlie the development and manifestation of psychiatric illness, specifically disorders on the affective spectrum including alcohol use disorders, drug abuse and anxiety disorders. The lab has expertise in studying neurotransmission from the level of signaling in individual cells through behavior utilizing a variety of techniques including: whole-cell electrophysiology, in vivo and ex vivo fast-scan cyclic voltammetry (FSCV), circuit manipulations (optogenetics, chemogenetics, caspase ablation), and behavioral assays.  There are several ongoing projects in the lab. One area we are focused on explores the role of neurons in the central nucleus of the amygdala (CeA) that express the neuropeptide neurotensin and the role these neurons play in alcohol related phenotypes. Additionally we are interested in exploring how norepinephrine modulates neurotransmission within the brain and how the norepinephrine system itself is modulated in models of substance abuse and post-traumatic stress. Beyond these studies, we are actively engaged in several other collaborative projects with other labs at UNC, as well as around the world.


The McGinty lab uses structural biology, protein chemistry, biochemistry, and proteomics to study epigenetic signaling through chromatin in health and disease. Chromatin displays an extraordinary diversity of chemical modifications that choreograph gene expression, DNA replication, and DNA repair – misregeulation of which leads to human diseases, especially cancer. We prepare designer chromatin containing specific combinations of histone post-translational modifications. When paired with X-ray crystallography and cryo-electron microscopy, this allows us to interrogate mechanisms underlying epigenetic signaling at atomic resolution.


Research in the lab focuses on how a single genome gives rise to a variety of cell types and body parts during development. We use Drosophila as a model organism to investigate (1) how transcription factors access DNA to regulate complex patterns of gene expression, and (2) how post-translational modification of histones contributes to maintenance of gene expression programs over time. We combine genomic approaches (e.g. chromatin immunoprecipitation followed by high-throughput sequencing) with Drosophila genetics and transgenesis to address both of these questions. Defects in cell fate specification and maintenance of cell identity often occur in human diseases, including cancer.


Dr. Meeker’s research is focused on the mechanisms of HIV neuropathogenesis and the development of therapeutic strategies for the treatment of neuroinflammation. Inflammatory changes within the brain caused by the viral infection initiate a toxic cascade that disrupts normal neural function and can eventually lead to neuronal death. To explore the mechanisms responsible for this damage, we investigate changes in calcium homeostasis, glutamate receptor function and inflammatory responses in primary neuronal, microglial and macrophage cultures. New therapeutic approaches targeted to signal transduction pathways and calcium regulation that protect the neurons and reduce inflammation are under investigation.


Our group studies the molecular epidemiology and pathogenesis of malaria and other vector-borne diseases.   We study malaria-infected individuals and populations in the Democratic Republic of the Congo, Malawi, Thailand, Cambodia, India, and the Gambia in order to understand the evolution and spread of drug resistance and the pathogenesis of malaria in pregnant women.   We also study parasite iron metabolism and cytoadherence.   Recently, we have begun working on vector-parasite interactions for tick-borne diseases in the US and for Chagas’ disease in Latin America.


We study the mechanisms by which innate immunity detects virulence factor activity in pathogenic bacteria. Research focuses on how macrophages detect bacterial type III secretion systems through the inflammasome, which activates Caspase-1, promoting secretion of the cytokines IL-1b and IL-18, as well as pyroptotic cell death. We manipulate bacterial virulence genetically and probe how this alters innate immune detection during infection. This focus joins the fields of microbial pathogenesis and immunology, utilizing the knowledge and tools of both disciplines.


Miller’s research group focuses on topics in integrative biophysics: physics applied to biology at the level of cells to organisms. In particular, the group is interested in the role of fluid forces during locomotion and morphogenesis. One ongoing project is focused on understanding the aerodynamics of flight in the smallest insects. Another current project investigates the role of fluid forces during the development of the embryonic vertebrate heart.


Molecular genetic analysis of virulence of Yersinia and Klebsiella: My laboratory uses Yersinia enterocolitica, Y. pestis, and Klebsiella as model systems to study bacterial pathogenesis. The long-term goals of our work are to understand the bacteria-host interaction at the molecular level to learn how this interaction affects the pathogenesis of infections and to understand how these pathogens co-ordinate the expression of virulence determinants during an infection. To do this we use genetic, molecular and immunological approaches in conjunction with the mouse model of infection.


My laboratory studies diffuse gliomas, devastating primary tumors of the central nervous system for which few effective drugs are currently available.  We utilize genetically engineered mice, cell culture, and human tumor model systems to explore the molecular pathogenesis of gliomas.  We utilize animal model systems to develop drugs and diagnostic markers for their individualized therapy.  Rotating students gain experience with multiple techniques, including cell culture, molecular biology, genomics, genetic lineage tracing, fluorescence microscopy, and digital image analysis.


My work focuses on the role of plant pathogens in (A) controlling or facilitating biological invasions by plants, (B) structuring plant communities, and (C) modulating the effects of global change on terrestrial ecosystems.  My group works on viruses, bacteria, and fungi that infect wild plants, chiefly grasses and other herbaceous species. Ultimately, I am interested in the implications of these processes for the sustainable provisioning of ecosystem services and for the conservation of biological diversity.


We identify genetic variants that influence common human traits with complex inheritance patterns, and we examine the molecular and biological mechanisms of the identified variants and the genes they affect. Currently we are investigating susceptibility to type 2 diabetes and obesity, and variation in cholesterol levels, body size, body shape, and metabolic traits. We detect allelic differences in chromatin structure and gene expression and examine gene function in human cell lines and tissues. In addition to examining the primary effects of genes, the lab is exploring the interaction of genes with environmental risk factors in disease pathogenesis. Approaches include genome-wide association studies, molecular biology, cell biology, genetic epidemiology, sequencing, and bioinformatic analysis of genome-wide data sets.


The work in my laboratory focuses on the molecular biology of human papillomaviruses (HPV), small DNA viruses that exhibit epithelial tropism. Certain types of HPV are considered the causative agents of cervical cancer and are also associated with cancers of the anus, oropharynx and esophagus.  My lab is interested in defining mechanisms that regulate the productive phase of the HPV life cycle, which is restricted to differentiating epithelia and includes viral genome amplification, late gene expression and virion production. Using various methods of epithelial differentiation, we are studying how HPV proteins modulate cell signaling pathways, including the DNA damage response and apoptosis, to facilitate viral replication, which in turn contributes to viral pathogenesis and possibly transformation. I will be accepting rotation students beginning in the winter of 2010.


How does a virus gain control over the host cell? My laboratory is interested in answering this question at the molecular level. By combining molecular biology and virology with new technologies (e.g. mass spectrometry, next generation sequencing), we investigate the mechanisms utilized by viruses to hijack infected cells. By understanding the specific function(s) of viral proteins during infection, we identify strategies used by viruses for deregulation of host cell processes. We use this information to characterize novel features of cell signaling pathways during infection, and to identify potential targets for anti-viral therapeutics.


Function, expression and trafficking GABA-A receptors in the CNS; effects of chronic ethanol exposure that leads to ethanol tolerance and dependence; role of endogenous neurosteroids on ethanol action and ethanol-induced adaptations. Role of neuroactive steroids in neuropsychiatric disease, including addiction, depressive disorders, anxiety disorders, inflammatory disorders.


We embrace an interdisciplinary approach to data science focused on networks and network representations, using mathematical models and statistical principles to develop computational tools for real-world data. With “nodes” representing objects of interest and “edges” that connect the nodes representing relationships or similarities, the concept of a network can be flexibly used across many applications. Our collaborations have included researchers in Biostatistics, Epidemiology, Infectious Diseases, Neuroscience, and Pharmacology.


Chlamydia trachomatis is the most common sexually transmitted bacterial pathogen that causes Fallopian tube inflammation and subsequent tubal infertility in women.  Our current research interest is to investigate the role of an innate immune responses to chlamydial infection and its role in genital tract pathology in a mouse model of genital infection.  Specifically, we are interested in delineating pathogen recognition by the host, signaling pathways that lead to the induction of innate immune cytokines in vitro and their downstream cellular effects in vivo.  We are specifically interested in understanding the contribution type I IFN, IL-1 activation, caspases and damage associated molecular patterns in pathogenesis. The identification of host molecules involved in amplification of the inflammatory response during infection, would serve as biomarkers and therapeutic targets to prevent reproductive sequelae in women infected with Chlamydia.


The main goal of the Nagarajan lab research program focuses on how the innate branch of the immune system regulates adaptive immunity, as it relates to the pathogenesis of autoimmune disease such as lupus or rheumatoid arthritis (RA)-induced cardiovascular disease.   IgG-Fcgamma receptor (FcgR)-mediated signaling is critical for mediating host defense against infectious disease, but they also mediate disease pathology in autoimmunity and atherosclerosis. Specifically, we are studying the role of IgG-Fcgamma receptor (FcgR) signaling network in innate immune cells activation that contributes to autoantibody production and T cell subset activation associated with autoimmune, and cardiovascular diseases.  We are using a repertoire of relevant knockout mouse and humanized FcgR mouse models to address the questions of how FcgR-mediated signaling promotes autoimmune disease-induced atherosclerosis. As a translational component, we are collaborating with rheumatologists and cardiologists to analyze changes in innate and T cell subsets in patients with lupus or RA, who has premature atherosclerosis.


The overall focus of the laboratory is to study the role of microRNA (miRNA) in the post-transcriptional modulation of the mucosal immune response. We are particularly interested in how miRNA modulates myeloid inflammatory cell (monocytes, macrophages, dendritic cells) and osteoclast differentiation and function. We are also interested in characterizing miRNA linked to the inflammatory response against periodontal pathogens in-vivo and in-vitro.


Our lab seeks to better understand the maturation and regulation of a group of human lipases.  We aim to uncover how these lipases properly fold and exit the ER, and how their activity is subsequently regulated.  We study the membrane-bound and secreted proteins that play a role in lipase regulation.  Our research can potentially impact human health as biochemical deficiencies in lipase activity can cause hypertriglyceridemia and associated disorders, such as diabetes and atherosclerosis.  We are an interdisciplinary lab and aim to address these questions using a variety of techniques, including membrane protein biochemistry, enzymology, and structural and molecular biology.


My laboratory has two main interests: 1) Regulation of P2Y receptor signaling and trafficking in epithelial cells and platelets. Our laboratory investigates the cellular and molecular mechanisms by which P2Y receptors are differentially targeted to distinct membrane surfaces of polarized epithelial cells and the regulation of P2Y receptor signaling during ADP-promoted platelet aggregation. 2) Antibiotic resistance mechanisms. We investigate the mechanisms of antibiotic resistance in the pathogenic bacterium, Neisseria gonorrhoeae. Our laboratory investigates how acquisition of mutant alleles of existing genes confers resistance to penicillin and cephalosporins. We also study the biosynthesis of the gonococcal Type IV pilus and its contribution to antibiotic resistance.


Nichols, Timothy C.
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Publications
RESEARCH INTEREST
Molecular Biology, Pathology

My research interests include the role of von Willebrand factor in thrombosis and atherosclerosis. Our current lab work focuses on the molecular biology of porcine von Willebrand factor.


Understanding how cells communicate and co-ordinate during development is a universal question in biology. My lab studies the cell to cell signaling systems that control plant stem cell production.  Plants contain discrete populations of self-renewing stem cells that give rise to the diverse differentiated cell types found throughout the plant.  Stem cell function is therefore ultimately responsible for the aesthetic and economic benefits plants provide us. Stem cell maintenance is controlled by overlapping receptor kinases that sense peptide ligands. Receptor kinase pathways also integrate with hormone signaling in a complex manner to modulate stem cell function.  My lab uses multiple approaches to dissect these networks including; genetics, genomics, CRISPR/Cas9 genome editing, live tissue imaging, and cell biological and biochemical methods.  This integrated approach allows us to gain an understanding of the different levels at which regulatory networks act and how they contribute to changes in form and function during evolution.


Nylander-French, Leena
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Publications
PHD PROGRAM
Toxicology

My research focuses on understanding the relationship between dermal and inhalation exposure and the effect of individual genetic differences on the function of enzymes that detoxify hazardous agents and that affect the development of disease. My research group has pioneered approaches to quantitatively measure skin and inhalation exposures to toxicants; additionally, my group has developed sophisticated exposure modeling tools using mathematical and statistical principles in an effort to standardize and improve exposure and risk assessment.


Modern Technologies from next-gen sequencing to high resolution imaging have advanced our knowledge of kidney development, function, and disease. We are among the pioneers utilizing techniques such as CHIP-seq, RNA-seq, modern genome editing, and imaging to understand how regulatory programs control progenitor populations during kidney development. Our goal is to understand how these programs contribute to progenitor specification and maintenance, and how they are altered during disease and aging. Our ultimate goal is translational applications of our research to develop new therapeutics and regenerative strategies.


The overall focus of research in my laboratory is to improve the diagnosis and treatment of airway diseases, especially those that result from impaired mucociliary clearance. In particular, our efforts focus on the diseases cystic fibrosis and primary ciliary dyskinesia, two diseases caused by genetic mutations that impair mucociliary clearance and lead to recurrent lung infections. The work in our laboratory ranges from basic studies of ciliated cells and the proteins that make up the complex structure of the motile cilia, to translational studies of new drugs and gene therapy vectors. We use a number of model systems, including traditional and inducible animal models, in vitro culture of differentiated mouse and human airway epithelial cells, and direct studies of human tissues. We also use a wide range of experimental techniques, from studies of RNA expression and proteomics to measuring ciliary activity in cultured cells and whole animals.


Paine, Mary
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Publications
PHD PROGRAM
Toxicology

The Paine group has two major research interests: (1) mechanisms underlying drug-xenobiotic interactions and (2) pharmacokinetic/toxicokinetic characterization of novel anti-parasitic agents.


Non-Mendelian genetics including, meiotic drive, parent-of-orifin effects and allelic exclusion.


The overall goal of our laboratory is to understand the molecular interface between cell signaling and adhesion receptors in blood diseases and cancer in order to develop novel therapeutic targets and approaches. One area of study is platelets because they become activated by cellular signals and adhere to each other and the blood vessel wall via specific adhesion receptors. These events can block blood flow, causing heart attacks and stroke, the leading causes of death in the US. Another area of research is sickle cell disease, since red blood cells in these patients are abnormally adhesive and also cause blood vessel blockages. A third area is cancer since cancer cells use similar cellular signals and adhesion receptors in tumorigenesis and metastasis. Our work involves a wide array  of technologies that include molecular, structural and cellular approaches as well as clinical/translational studies with human patients.


Our research is focused in the methodological development and integrated analysis of high throughput genetic and genomic studies. I previously lead the development of algorithms and content resulting in ProsignaTM, the only CE marked and FDA 510(k) cleared breast cancer diagnostic assay for FFPE tissue. We are currently involved in similar diagnostic development in multiple clinical trials where genomics are modeled to predict clinical outcomes in cancer.

In a separate role, I currently direct the sequencing, microarray, and other genomics analysis in the Bioinformatics Shared Resource at the Lineberger Comprehensive Cancer Center. The Bioinformatics Shared Resource provides consultation and analytical services primarily for the Cancer Center, but is also involved in collaborations across multiple departments and institutions. This role has brought a number of opportunities for technology development, primarily for sequencing data analysis. Here we are continuously developing algorithms and software to maximize the information content from novel sequencing assays.


Our research is focused in the methodological development and integrated analysis of high throughput genetic and genomic studies. I previously lead the development of algorithms and content resulting in ProsignaTM, the only CE marked and FDA 510(k) cleared breast cancer diagnostic assay for FFPE tissue. We are currently involved in similar diagnostic development in multiple clinical trials where genomics are modeled to predict clinical outcomes in cancer.

 

In a separate role, I currently direct the sequencing, microarray, and other genomics analysis in the Bioinformatics Shared Resource at the Lineberger Comprehensive Cancer Center. The Bioinformatics Shared Resource provides consultation and analytical services primarily for the Cancer Center, but is also involved in collaborations across multiple departments and institutions. This role has brought a number of opportunities for technology development, primarily for sequencing data analysis. Here we are continuously developing algorithms and software to maximize the information content from novel sequencing assays.


The Patterson laboratory has 4 major focuses, each of which is funded by at least one major grant. Our longest ongoing project focuses on blood vessel growth and development, and in particular how bone morphogenetic protein signaling regulates vascular development. A second ongoing project in the laboratory is to understand at a fundamental level the cellular response to proteotoxic stress. The third major focus of our laboratory studies cardiac-specific ubiquitin ligases that regulate cardiac hypertrophy and metabolism. Finally, we have begun a human translational study that takes advantage of our expertise in genomics, proteomics, and genetics to develop an integrated DNA/RNA/protein profile database of patients with heart disease.


We are a comprehensive, collaborative group with a primary focus on lead and early drug discovery for oncology and epigenetic targets and pathways. Our research applies reagent production, primary assay development, high-throughput screening, biophysics, and exploratory cell biology to enable small molecule drug discovery programs in solid partnership with collaborators, both within the Center for Integrative Chemical Biology and Drug Discovery and across the UNC campus. We apply small molecule hit discovery to highly validated biochemical targets as well as phenotypic cell-based assays. Our methods include various fluorescence-based readouts and high content microscopy. Examples of some of our collaborative small molecule discovery programs include, inhibition of chromatin methyl-lysine reader proteins, hit discovery for small GTPases such as K-Ras and Gaq, inhibitors of inositol phosphate kinases, inhibitors of protein-protein interactions involving CIB1 and MAGE proteins, and several cell-based efforts including a screen for compounds that enhance c-Myc degradation in pancreatic cancer cells. In addition, we are developing a DNA-encoded library approach for hit discovery to complement traditional high-throughput screening. Our ultimate goal is discovery of new chemical probes and medicines for exploratory biology and unmet medical needs, respectively.


The development of metastases is the cause of death in nearly all cancer patients, yet the mechanisms driving metastatic biology remain poorly understood. Also, few cancer therapeutics are being developed to specifically control this problem. My laboratory is interested in discovering novel mechanisms that drive metastatic biology, and in utilizing RNA interference (RNAi) strategies (such as nanoparticle delivery of miRNAs/siRNAs) to control this process. We will apply integrative analysis of large bioinformatic datasets, in vitro studies for mechanistic validation, and in vivo metastasis models to assess therapeutic efficacy of our RNAi approaches.


Peden, David B.
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Publications
RESEARCH INTEREST
Toxicology

Translational and clinical research in environmental lung disease.


Cell adhesion, signal transduction, and cytoskeletal regulation during embryogenesis and in cancer.  We focus on the regulation of cadherin-based cell-cell adhesion, and on Wnt signaling and its regulation by the tumor suppressor APC.


The focus of my lab is to characterize the biological diversity of human tumors using genomics, genetics, and cell biology, and then to use this information to develop improved treatments that are specific for each tumor subtype and for each patient. A significant contribution of ours towards the goal of personalized medicine has been in the genomic characterization of human breast tumors, which identified the Intrinsic Subtypes of Breast Cancer. We study many human solid tumor disease types using multiple experimental approaches including RNA-sequencing (RNA-seq), DNA exome sequencing, Whole Genome Sequencing, cell/tissue culturing, and Proteomics, with a particular focus on the Basal-like/Triple Negative Breast Cancer subtype. In addition, we are mimicking these human tumor alterations in Genetically Engineered Mouse Models, and using primary tumor Patient-Derived Xenografts, to investigate the efficacy of new drugs and new drug combinations. All of these genomic and genetic studies generate large volumes of data; thus, a significant portion of my lab is devoted to using genomic data and a systems biology approach to create computational predictors of complex cancer phenotypes.


It is estimated that less than 2% of the human genome codes for a functional protein.  Scattered throughout the rest of the genome are regulatory regions that can exert control over genes hundreds of thousands of base pairs away through the formation of DNA loops.  These loops regulate virtually all biological functions but play an especially critical role in cellular differentiation and human development. While this phenomenon has been known for thirty years or more, only a handful of such loops have been functionally characterized.  In our lab we use a combination of cutting edge genomics (in situ Hi-C, ATAC-seq, ChIP-seq), proteomics, genome editing (CRISPR/Cas), and bioinformatics to characterize and functionally interrogate dynamic DNA looping during monocyte differentiation.  We study this process both in both healthy cells and in the context of rheumatoid arthritis and our findings have broad implications for both cell biology as well as the diagnosis and treatment of human disease.


My lab is driven to understand the neuronal pathologies underlying neurodevelopmental disorders, and to use this information to identify novel therapeutics.  We focus our research on monogenic autism spectrum disorders, including Angelman, Rett, and Pitt-Hopkins syndromes.  We employ a diverse number of techniques including: electrophysiology, molecular biology, biochemistry, mouse engineering, and in vivo imaging.


My laboratory, located in the Cystic Fibrosis/Pulmonary Research and Treatment Center in the Thurston-Bowles building at UNC, is interested in how respiratory viruses infect the airway epithelium of the conducting airways of the human lung.


My graduate students and I use the formalism of equilibrium thermodynamics and the tools of molecular biology and biophysics to understand how nature designs proteins.


Our group develops computational methods for the analysis of high throughput sequence data.  Our focus is on transcriptome analysis and its applications.


Our group develops computational methods for the analysis of high throughput sequence data. Our focus is on transcriptome analysis and its applications.


Pukkila, Patricia
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Publications
RESEARCH INTEREST
Genetics, Genomics

The long term goal of our research is to understand mechanisms underlying homologous chromosome pairing and genetic recombination during meiosis. We have developed the basidiomycete fungus Coprinus cinereus as a model system for analysis of meiosis. We are currently utilizing transcriptional profiling of the recently annotated genome to analyze the genetic controls of chromosome pairing. We have also constructed a high-resolution genetic map of the 13 sequenced chromosomes to examine chromosomal sites that act autonomously to initiate synapsis.


We study the behavior of individual cells with a specific focus on “irreversible” cell fate decisions such as apoptosis, senescence, and differentiation. Why do genetically identical cells choose different fates? How much are these decisions controlled by the cell itself and how much is influenced by its environment? We address these questions using a variety of experimental and computational approaches including time-lapse microscopy, single-molecule imaging, computational modeling, and machine learning. Our ultimate goal is to not only understand how cells make decisions under physiological conditions—but to discover how to manipulate these decisions to treat disease.


The goal of my research is to define molecular mechanisms of immune cell co-option by cancer cells, with the hope of identifying novel targets for immune cell reprogramming. Central to our approach is analysis immune cell subtypes in KRas-driven models of pancreatic cancer. We use cell and animals models to study signals important for pro-tumorigenic activity of immune cells, as well as define role of physiologically relevant oncogenic mutations in driving these signals and enabling immune escape.


Our laboratory is interested in developing innovative approaches to regenerate or repair an injured heart. Our goal is to understand the molecular basis of cardiomyocyte specification and maturation and apply this knowledge to improve efficiency and clinical applicability of cellular reprogramming in heart disease. To achieve these goals, we utilize in vivo modeling of cardiac disease in the mouse, including myocardial infarction (MI), cardiac hypertrophy, chronic heart failure and congenital heart disease (CHD). In addition, we take advantage of traditional mouse genetics, cell and molecular biology, biochemistry and newly developed reprogramming technologies (iPSC and iCM) to investigate the fundamental events underlying the progression of various cardiovascular diseases as well as to discover the basic mechanisms of cell reprogramming.


Our laboratory investigates the role of the Epstein-Barr virus in the etiology of human disease. EBV is a ubiquitous infectious agent, which is associated with specific malignancies including Burkitt’s lymphoma, Hodgkin’s lymphoma, and nasopharyngeal carcinoma (NPC), which develop with high incidence in endemic areas. EBV is etiologic for post-transplant lymphoma and also causes the AIDS-associated disease, hairy leukoplakia (HLP). We have identified three viral genes, which are consistently expressed and have identified a new family of transcripts that are expressed at particularly high levels in NPC tissue.  These new mRNAs are intricately spliced and contain several new open reading frames which could potentially code for protein. We have shown one of these open reading frames does encode a protein that is expressed at high levels in EBV associated cancers. Current studies are investigating the potential functions of this gene using the two hybrid analysis in yeast cells and by determining its intracellular location with confocal microscopy.


The end joining pathway is a major means for repairing chromosome breaks in vertebrates.  My lab is using cellular and cell-free models to learn how end joining works, and what happens when it doesn’t.


Identification of airway epithelial stem cells; innate immunity in the airway; the pathophysiology of post-lung transplant ischemia reperfusion injury and bronchiolitis obliterans syndrome.


The Redinbo Laboratory examines dynamic cellular processes using structural, chemical, molecular and cell biology. Our goals are to discover new drugs and to elucidate molecular pathways essential to human disease.  Current projects include developing the first drugs that target the human microbiome, unraveling the nature of innate immunity in the human lung, and discovering how microbial systems exchange genes, including those that encode antibiotic resistance.


Regulation of plant development:  We use techniques of genetics, molecular biology, microscopy, physiology, and biochemistry to study how endogenous developmental programs and exogenous signals cooperate to determine plant form.  The model plant Arabidopsis thaliana has numerous technical advantages that allow rapid experimental progress.  We focus on how the plant hormone auxin acts in several different developmental contexts.  Among questions of current interest are i) how auxin regulates patterning in embryos and ovules, ii) how light modifies auxin response, iii) how feedback loops affect kinetics or patterning of auxin response, iv) how flower opening and pollination are regulated, and v) whether natural variation in flower development affects rates of self-pollination vs. outcrossing.


Two dynamically interacting sets of mechanisms govern tissue-specific gene expression and cell growth. 1) mechanisms in lineage biology regulate stem cells and their descendents, processes that define the repertoire of genes available to be regulated and 2) signal transduction mechanisms, induced by the synergistic effects of extracellular matrix components and soluble signals (hormones, growth factors), regulate the expression of the available genes. Studies in the lab focus on both classes of mechanisms in normal versus neoplastic tissue.


Reissner, Kathryn
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Publications
PHD PROGRAM
Neurobiology

Research in our lab is focused on understanding how cocaine abuse affects glial cell physiology, in particular neuron-astrocyte communication.  We utilize the rat cocaine self-administration/reinstatement model, which allows us to test hypotheses regarding not only how chronic cocaine use affects properties of astrocytes and the tripartite synapse, but also how compounds affecting glial cells may influence synaptic processing within the brain’s reward neurocircuitry and behavioral measures of drug seeking.


My research interests include genetic and genomic approaches to understanding lymphoma biology and treatment.  As members the Center for Pharmacogenomics and Individualized Therapy (CPIT), we are involved in a project using genome-wide association studies to identify SNPs associated with sensitivity to a variety of chemotherapy agents.  Also, we are using genomic strategies to characterize a canine model of lymphoma in pet dogs that could be used to provide a more representative animal model for therapeutic trials.  I am also the UNC principal investigator on several clinical trials that focus on HIV related lymphoma.


In the Richardson Lab, we study bacterial physiology as it pertains to human disease.  Primarily, we focus on the metabolic adaptations mounted by bacterial pathogens (e.g. Staphylococcus aureus and Streptococcus spp.) to avoid clearance by host innate immunity.  We use a combination of bacterial genetics, molecular biology, microbial physiology and computational modeling to probe the metabolic state of pathogens during infection.  Given the complexities of host/pathogen interactions, metabolic flexibility in invading pathogens is a crucial aspect of bacterial virulence.


The Robinson lab currently explores the neurodynamics of reinforcement pathways in the brain by using state-of-the-art, in vivo recording techniques in freely moving rats. Our goal is to understand the interplay of mesostriatal, mesocortical and corticostriatal circuits that underlie action selection, both in the context of normal development and function, and in the context of psychiatric disorders that involve maladaptive behavior, such as alcohol use disorder, adolescent vulnerability to drug use and addiction, cocaine-induced maternal neglect and binge-eating disorders.


The research in our lab is centered on understanding the mechanisms and principles of movement at the cellular level. Cytoskeletal filaments – composed of actin and microtubules – serve as a structural scaffolding that gives cells the ability to divide, crawl, and change their shape.  Our lab uses a combination of cell biological, biochemical, functional genomic, and  high resolution imaging techniques to study cytoskeletal dynamics and how they contribute to cellular motion.


The ultimate goal of our studies is to discover novel ways to treat human disease using G-protein coupled receptors.


Our laboratory applies molecular, biochemical, genetic and genomics approaches to understanding the mechanisms of environmental agent-related organ injury and carcinogenesis. Specifically, we are interested in nuclear receptor-mediated pathways in chemical carcinogenesis, oxidative DNA damage and repair, the role that alcohol and diet play in cancer, and the genetic determinants of the susceptibility to toxicant-induced liver injury. Through a combination of in vivo animal studies and experiments that utilize cellular and molecular models, we aim to better understand why certain chemicals cause cancer or organ damage in rodents and whether humans in general, or any susceptible sub-population in particular, are at risk from similar exposures.


Samet, James M.
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Publications
PHD PROGRAM
Toxicology
RESEARCH INTEREST
Immunology, Toxicology

Our laboratory is focused on the cellular and molecular mechanisms that control  inflammatory and adaptive responses induced by inhalation of ambient air pollutants. Projects focus on early events that result in the disregulation of signaling processes that regulate gene expression, specifically oxidative effects that disrupt signaling quiescence in human lung cells. Approaches include live-cell imaging of human lung cells exposed in vitro and ex-vivo and characterization of oxidative protein modifications.


We are engaged in studying the molecular biology of the human parvovirus adeno-associated virus (AAV) with the intent to using this virus for developing a novel, safe, and efficient delivery system for human gene therapy.


We have three main areas of research focus: (1) Nucleotide excision repair: The only known mechanism for the removal of bulky DNA adducts in humans. (2) DNA damage checkpoints:  Biochemical pathways that transiently block cell cycle progression while DNA contains damage.  (3) Circadian rhythm:  The oscillations in biochemical, physiological and behavioral processes that occur with the periodicity of about 24 hours.


Our long term goals are to better define mechanisms of chronic intestinal inflammation and to identify areas for therapeutic intervention. Research in our laboratories is in the following four general areas: 1) Induction and perpetuation of chronic intestinal and extraintestinal inflammation by resident intestinal bacteria and their cell wall polymers, 2) Mechanisms of genetically determined host susceptibility to bacterial product,. 3) Regulation of immunosuppressive molecules in intestinal epithelial cells and 4) Performing clinical trials of novel therapeutic agents in inflammatory bowel disease patients.


Savoldo, Barbara
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Publications

My research interests are in the immunology and pathogenesis of Epstein-Barr virus (EBV) associated lymphomas developing in immunosuppressed patients. I have studied the use of EBV specific cytotoxic T-cells (CTLs) for therapy of post-transplant EBV-associated lymphoproliferative disease (PTLD). I am also interested in the preclinical development of cancer immunotherapy approaches for hematological and solid tumors, specifically by using T cells as platform for exploring genetic immune-manipulations to redirect them to tumors by transgenic expression of alpha-betaTCRs or of chimeric antigen/tumor-specific receptors (CARs). My research also focus on gene modifications aimed at improving the homing of T cells to tumor cells , improving their proliferation and persistence and finally overcoming  the inhibitory effect of the tumor environments, including effects of regulatory T (Treg) cells.


The Schisler Lab is geared towards understanding and designing therapies for diseases involving proteinopathies- pathologies stemming from protein misfolding, aggregation, and disruption of protein quality control pathways. We focus on cardiovascular diseases including the now more appreciated overlap with neurological diseases such as CHIPopathy (or SCAR16, discovered here in our lab) and polyQ diseases. We use molecular, cellular, and animal-based models often in combination with clinical datasets to help drive our understanding of disease in translation to new therapies.


The Schrider Lab develops and applies computational tools to use population genetic datasets to make inferences about evolutionary history. Our research areas include but are not limited to: characterizing the effects natural selection on genetic variation within species, identifying genes responsible for recent adaptation, detecting genomic copy number variants and other weird types of mutations, and adapting machine learning tools for application to evolutionary questions. Study organisms include humans, the fruit fly Drosophila melanogaster and its relatives, and the malaria vector mosquito Anopheles gambiae.


My lab is interested in mechanisms that (1) fine tune gene expression and (2) coordinate transcription and RNA processing in eukaryotes. Our work is based on molecular, genetic and biochemical analysis of the suppressor of sable gene of Drosophila.


Segal, Rick
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Publications
PHD PROGRAM
Neurobiology
RESEARCH INTEREST
Neurobiology

Movement control and neuroplasticity in able-bodied humans and humans with neurological dysfunction are the focus of research program. More specifically, would like to understand the basic interaction of spinal circuits and supraspinal systems and adaptability of these interactions during upper limb movements and locomotion. Studies to understand this interaction include anatomical (dissection and MRI), electrophysiological (EMG and reflex) and biomechanical studies to identify the neuromuscular elements that interact with spinal circuits, and what principles govern their coordination. Studies are also underway to understand plasticity of spinal circuits, including those underlying stretch reflexes in both able-bodied humans and humans with spinal cord injury. These studies utilize operant conditioning of reflexes that may be useful for the functional training of newly formed connections in spinal cord injured patients if regeneration can be induced. The operant conditioning studies will also be useful in determining the relationship of spinal circuits and voluntary movement.


Genome instability is a major cause of cancer. We use the model organism Drosophila melanogaster to study maintenance of genome stability, including DNA double-strand break repair, meiotic and mitotic recombination, and characterization of fragile sites in the genome.  Our primary approaches are genetic (forward and reverse, transmission and molecular), but we are also using biochemistry to study protein complexes of interest, genomics to identify fragile sites and understand the regulation of meiotic recombination, fluorescence and electron microscopy for analysis of mutant phenotypes, and cell culture for experiments using RNA interference.


The Serody laboratory focuses on tumor and transplant immunology studies using both animal models and translational work with clinical samples. We have performed pioneering work in both of these areas. Our laboratory was the first to describe a role for migratory proteins in the biology of acute GVHD. We were the first group to use eGFP transgenic mice generated in part by our group to track the migration of donor cells after transplant. This work showed a critical role for lymphoid tissue in the activation of donor T cells. Most recently we have been the first group to demonstrate the absence of ILC2 cells in the GI tract after all types of transplant and we have generated novel studies into the ILC2 niche in the bone marrow. For our tumor work we were one of the first groups to use genomic evaluations of the tumor microenvironment to characterize the immune response in cancer models. We were the first group to demonstrate how to enhance checkpoint inhibitor therapy in triple negative breast cancer models and have been one of the leading groups in performing genomic evaluations using TCGA data. Finally, we are one of the leading groups in the world characterizing the role of B cells in the anti-tumor immune response.


The Shaikh lab aims to understand how differing dietary fatty acids regulate outcomes associated with immunity and metabolism in the context of obesity, type 2 diabetes, and cardiovascular diseases. The lab conducts studies at the human level and in mouse models.  We are currently focused on the mechanisms by which omega-3 fatty acids improve chronic inflammation and humoral immunity upon viral infection in obesity. We are also elucidating how select fatty acids disrupt the biophysical organization of the inner mitochondrial membrane of differing cell types and thereby respiratory activity.


My laboratory studies chemically mediated interactions between microbes, particularly those that lead to alterations in bacterial development. In the natural world, interspecies chemical communication contributes to the stability and function of complex microbial communities. We explore the mechanisms and molecules that microbes use to influence their microbial neighbors both in the laboratory and in natural environments using genetics, microscopy, chemical imaging, and next generation sequencing. Our goal is to gain insights into microbial ecology, identify compounds with novel bioactivities, and obtain chemical tools to manipulate bacterial behavior to our benefit.


My work is centered upon the characterization of the large mucin gene products and the complexes they make which are essential for the formation of the mucus gels vital for epithelial protection and function. This work is focused around the human lung where there are many human diseases including asthma, cystic fibrosis, and chronic bronchitis in which these glycoconjugates are centrally implicated. Our studies are broad ranging and seek to build up a picture of the chemistry of these complex phenotypes, the network of their interactions that constitutes a mucosal surface and the mechanisms of their biosynthesis, assembly and secretion.  The laboratory is established with a wide range of methods including MALDI and ESI mass spectrometry, electron and atomic force microscopy, hydrodynamics, theoretical molecular dynamics and a variety of surface physics tools.


We seek to understand how information is encoded and dynamically utilized in immune cells from healthy and disease prone intestines (The Inflammatory Bowel Diseases: Crohn’s disease and Ulcerative Colitis). Our lab is multi-disciplinary and combines high-throughput genomics with innate immunity and microbiology. We focus specifically on genes that regulate response to the bacteria that normally reside in our intestines. Many of these genes make products that regulate the immune system in the intestine. These products defend the intestine against the attack of foreign materials; such as bacteria that live in the intestine. We use genome-sequencing technology to precisely identify regions throughout the genome that are potential ‘on’ or ‘off’ switches for these genes. There is a fine balance between the genes that produce inflammatory substances that are necessary to kill bacteria and genes that produce anti-inflammatory substances that are important to prevent damage to the intestine. If this balance between inflammatory and anti-inflammatory substance production in the intestine is disrupted, IBD may result. Our lab focuses on understanding how these important controllers of inflammation are turned on and off in IBD. We also study how inflammatory and anti-inflammatory signals impact disease severity, progression and response to therapy in individuals with IBD. This information has the potential to increase our understanding of causes of IBD (personalized medicine) and to contribute to the development of new treatments.


The Shiau Lab is integrating in vivo imaging, genetics, genome editing, functional genomics, bioinformatics, and cell biology to uncover and understand innate immune functions in development and disease. From single genes to individual cells to whole organism, we are using the vertebrate zebrafish model to reveal and connect mechanisms at multiple scales. Of particular interest are 1) the genetic regulation of macrophage activation to prevent inappropriate inflammatory and autoimmune conditions, and 2) how different tissue-resident macrophages impact vertebrate development and homeostasis particularly in the brain and gut, such as the role of microglia in brain development and animal behavior.


My work is centered upon the characterization of the large mucin gene products and the complexes they make which are essential for the formation of the mucus gels vital for epithelial protection and function. This work is focused around the human lung where there are many human diseases including asthma, cystic fibrosis, and chronic bronchitis in which these glycoconjugates are centrally implicated. Our studies are broad ranging and seek to build up a picture of the chemistry of these complex phenotypes, the network of their interactions that constitutes a mucosal surface and the mechanisms of their biosynthesis, assembly and secretion.  The laboratory is established with a wide range of methods including MALDI and ESI mass spectrometry, electron and atomic force microscopy, hydrodynamics, theoretical molecular dynamics and a variety of surface physics tools.


The Singleton Laboratory is interested in understanding the molecular basis for the develoment and transmission of microbial drug resistance and the discovery and exploitation of new strategies for controlling drug-resistant microorganisms. We develop and adapt synthetic chemistry and synthetic biology methods to provide new molecular tools — both biologically active small molecules and innovative platforms — for hypothesis-driven biological research and pharmaceutical discovery. These foundations of our program offers both chemically-oriented and biologically-oriented researchers new opportunities for the development of integrated, multi-disciplinary knowledge and technologies.


Our lab examines cytoskeletal dynamics, the molecules that regulate it and the biological processes it is involved in using live cell imaging, in vitro reconstitution and x-ray crystallography.  Of particular interest are the microtubule +TIP proteins that dynamically localize to microtubule plus ends, communicate with the actin network, regulate microtubule dynamics, capture kinetochores and engage the cell cortex under polarity-based cues.


Our lab has two areas of interest: the molecular basis of liver diseases and the biochemical mechanisms of disorders linked to intermediate filament gene mutations. We use biochemical, cell-based and in vivo approaches to identify potential disease targets and to understand their function and regulation. The major goal of our work is to promote the discovery of pharmacological agents that can slow or halt the progression of these diseases.


My primary research area is computational geometry, in which one studies the design and analysis of algorithms for geometric computation. Computational geometry finds application in problems from solid modeling, CAD/CAM, computer graphics, molecular biology, data structuring, and robotics, as well as problems from discrete geometry and topology.  Most of my work involves identifying, representing, and exploiting geometric and topological information that permit efficient computation.  My current focus is on applications of computational geometry in Molecular Biology and Geographic Information Systems (GIS). Examples of the former include docking and folding problems, and scoring protein structures using Delaunay tetrahedralization.


I study the ultimate and proximate factors controlling flexibility in reproductive behavior. Using songbirds as a system, I use field and laboratory studies to investigate the ecological cues regulating reproductive flexibility, the neural integration of these cues, and the neural mechanisms precipitating adaptive behavioral outcomes. Of particular interest is the study of courtship and mate-choice behavior and how the songbird brain integrates ecological and social information. I am also interested in how the timing of reproduction, reproductive effort, and family planning are controlled. I use high performance liquid chromatography for the measurement of central catecholamines and immunocytochemistry and microscopy for quantifying neuropeptides and the expression of immediate early genes as markers of neural activity.


Our laboratory studies signal transduction systems controlled by heterotrimeric G proteins as well as Ras-related GTPases using a variety of biophysical, biochemical and cellular techniques. Member of the Molecular & Cellular Biophysics Training Program.


Our primary research interest is to identify the mechanisms that regulate neural circuit organization and function at distinct stages of adult neurogenesis, and to understand how circuit-level information-processing properties are remodeled by the integration of new neurons into existing circuits and how disregulation of this process may contribute to various neurological and mental disorders. Our long-range goals are to translate general principles governing neural network function into directions relevant for understanding neurological and psychiatric diseases. We are addressing these questions using a combination of cutting-edge technologies and approaches, including optogenetics, high-resolution microscopy, in vitro and in vivo electrophysiology, genetic lineage tracing and molecular biology.


Stafford, Darrel W.
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Publications
PHD PROGRAM
Biology

My laboratory at present is working on the vitamin K cycle and vitamin K-dependent proteins.  The enzymes of the vitamin K cycle include, at a minimum two integral membrane proteins, both of which were purified and cloned by my laboratory.  One, the vitamin K epoxide reductase is the target of warfarin for which 40 million prescriptions are written each year in the US alone.  Polymorphisms in this gene are the best example to date of the use of genomics in molecular medicine.  We are also interested in purifying any additional components of this cycle and trying to understand the ~50% of patients whose genotype is not informative about warfarin dose.  In addition, we are interested in the mechanism of how factor VIIa works and the role of the extracellular matrix in coagulation.


We are a lab exploring how variations in the genome change the structure and development of the brain, and in doing so, create risk for neuropsychiatric illness. We study genetic effects on multiple aspects of the human brain, from macroscale phenotypes like gross human brain structure measured with MRI to molecular phenotypes like gene expression and chromatin accessibility measured with genome-sequencing technologies. We also use neural progenitor cells as a modifiable and high fidelity model system to understand how disease-associated variants affect brain development.


Our laboratory is examining the role of histone post-translational modifications in chromatin structure and function.  Using a combination of molecular biology, genetics and biochemistry, we are determining how a number of modifications to the histone tails (e.g. acetylation, phosphorylation, methylation and ubiquitylation) contribute to the control of gene transcription, DNA repair and replication.


Styblo, Miroslav
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Publications
PHD PROGRAM
Nutrition, Toxicology
RESEARCH INTEREST
Physiology, Toxicology

Dr. Styblo is a biochemist with background in nutritional biochemistry and biochemical toxicology. His research focuses on topics that require expertise in both nutrition and toxicology and typically involve a translational or interdisciplinary approach. His current research projects examine mechanisms and etiology of diseases associated with exposures to environmental toxins with main focus on cancer and diabetes associated with exposure to arsenic (a common drinking water contaminant), and on the role of diet or specific nutrients in prevention of these diseases.


My laboratory studies development and function of the human immune system and human liver, and HIV-1/HCV infection and immuno-pathogenesis.  1. Humanized mouse models to study human hamatopoietic stem cells (HSC), thymus and liver stem cells.   2. FoxP3 and regulatory T (Treg) cells in viral infection and immuno-pathogenesis.  3. Modeling immuno-pathogenesis and immuno-therapy of chronic HIV and HCV.


Research in my laboratory is directed toward achieving a better understanding of the mechanisms and pathogenesis associated with a variety of environmentally induced or genetically based birth defects. This information is then applied to development of preventative/ameliorative measures relative to these defects. Our interest in modeling human genetic malformation syndromes and opportunities for collaborative efforts with molecular geneticists who have produced transgenic mice and mice with targeted gene modification have proven productive in our attempt to better understand the developmental basis for a variety of malformations of the brain including anencephaly, holoprosencephaly, and hydrocephaly. Regarding teratogen-induced birth defects, our major emphasis is on Fetal Alcohol Spectrum Disorders (FASD).   Currently,  high resolution magnetic resonance imaging (MRI) is being utilized to identify, characterize, and correlate the craniofacial, ocular, otic and CNS dysmorphology that results from prenatal ethanol exposure at specific stages of embryogenesis. These studies are designed to inform human clinical research and to expand the diagnostic criteria for prenatal alcohol exposure.


I study complex traits using linkage, association, and genetic epidemiological approaches.  Disorders include schizophrenia (etiology and pharmacogenetics), smoking behavior, and chronic fatigue.


First, we study the complex HIV-1 population that exists within a person.  We use this complexity to ask questions about viral evolution, transmission, compartmentalization, and pathogenesis.  Second, we are exploring the impact of drug resistance on viral fitness and identifying new drug targets in the viral protein processing pathway.  Third, we participate in a collaborative effort to develop an HIV-1 vaccine.  Fourth, we are using mutagenesis to determine the role of RNA secondary structure in viral replication.


My laboratory focuses on understanding mechanisms of carcinogenesis, with emphasis on the role of DNA damage and repair. During the last few years, we have developed ultra-sensitive and highly specific mass spectrometry methods for measuring the DNA and hemoglobin adducts of vinyl chloride, crotonaldehyde, ethylene oxide, propylene oxide, styrene oxide, butadiene, malondialdehyde, cis-platin and O6-methyldeoxy-guanosine, as well as slotblot methods for AP sites and oxidative DNA damage. These methods have been applied to understanding critical mechanisms in carcinogenesis, as well as undertaking molecular epidemiology studies of workers in the butadiene and reinforced plastics industries. We are also examining changes in gene expression associated with oxidative stress and environmental chemical exposure.


Our lab studies the mechanisms facultative pathogens use to adapt to disparate and changing extracellular conditions. Our primary interest is in the ability of Vibrio cholerae, the causative agent of cholera, to persist in its native aquatic environment and also flourish in the host intestinal tract. We are addressing key questions about the role of cyclic diguanylate, a signaling molecule unique to and ubiquitous in bacteria, in the physiological adaptations of V. cholerae as it transits from the aquatic environment into a host. In addition, we are identifying and characterizing factors produced by V. cholerae during growth in a biofilm, a determinant of survival in aquatic environments, that contribute to virulence.  I will be accepting rotation students beginning in the winter of 2009.


The Tarantino lab studies addiction and anxiety-related behaviors in mouse models using forward genetic approaches. We are currently studying a chemically-induced mutation in a splice donor site that results in increased novelty- and cocaine-induced locomotor activity and prolonged stress response. We are using RNA-seq to identify splice variants in the brain that differ between mutant and wildtype animals. We are also using measures of initial sensitivity to cocaine in dozens of inbred mouse strains to understand the genetics, biology and pharmacokinetics of acute cocaine response and how initial sensitivity might be related to addiction. Finally, we have just started a project aimed at studying the effects of perinatal exposure to dietary deficiencies on anxiety, depression and stress behaviors in adult offspring. This study utilizes RNA-seq and a unique breeding design to identify parent of origin effects on behavior and gene expression in response to perinatal diet.


Tarran, Robert
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Publications
RESEARCH INTEREST
Cell Biology, Pathology, Physiology

A critical component of airways innate defense is the thin liquid layer lining airway surfaces, the periciliary liquid (PCL), that provides a low viscosity solution for ciliary beating and acts a lubricant layer for mucus transport. Normal airways appear to be able to sense the PCL volume and adjust ion channel activity accordingly.  The long term goal of this laboratory is to understand how homeostasis of PCL volume occurs in airway epithelia under normal and pathophysiological conditions. Currently, research in the Tarran lab is focused on three main areas: 1) Regulation of epithelial cell function by the extracellular environment, 2) Gender differences in cystic fibrosis lung disease and 3) The effects of cigarette smoke on epithelial airway ion transport.  We utilize cell biological and biochemical techniques coupled with in vivo translational approaches to address these questions.


Tarran, Robert
Website | Email
Publications
RESEARCH INTEREST
Cell Biology, Pathology, Physiology

A critical component of airways innate defense is the thin liquid layer lining airway surfaces, the periciliary liquid (PCL), that provides a low viscosity solution for ciliary beating and acts a lubricant layer for mucus transport. Normal airways appear to be able to sense the PCL volume and adjust ion channel activity accordingly. The long term goal of this laboratory is to understand how homeostasis of PCL volume occurs in airway epithelia under normal and pathophysiological conditions. Currently, research in the Tarran lab is focused on three main areas: 1) Regulation of epithelial cell function by the extracellular environment, 2) Gender differences in cystic fibrosis lung disease and 3) The effects of cigarette smoke on epithelial airway ion transport. We utilize cell biological and biochemical techniques coupled with in vivo translational approaches to address these questions.


Taylor, Anne Marion
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Publications
PHD PROGRAM
Neurobiology

Local mRNA translation is critical for axon regeneration, synapse formation, and synaptic plasticity. While much of research has focused on local translation in dendrites and in peripheral axons, less is known about local translation in smaller diameter central axons due to the technical difficulty of accessing them. We developed microfluidic technology to allow access to axons, as well as nascent boutons and fully functional boutons. We identified multiple transcripts that are targeted to cortical and hippocampal axons in rat (Taylor et al. J Neurosci 2009). Importantly, this work countered the prevailing view that local mRNA translation does not occur in mature axons. We are actively investigating transcripts in axons that may play a role in establishing proper synaptic connections. We are also using our technology to identify transcripts targeted to axons and boutons in human neurons. These studies are a critical step towards the identification of key genes and signaling molecules during synapse development, axonal regeneration, and proper circuit function.


The goal of our research is to identify signaling mechanisms that contribute to normal and pathophysiological cell growth in the cardiovascular system.  We study cardiac and vascular development as well as heart failure and atherosclerosis.


The Thakker Lab’s major research focus is in three related and yet distinct areas: (i) mechanisms of drug absorption/transport across intestinal epithelium, and (ii) Mechanism-based approaches to modulate intestinal tight-junction permeability, and (iii) Optimizing pediatric drug therapy by understanding drug disposition differences between adult and pediatric populations.  Multi-disciplinary approaches are employed in the group with strong emphasis on organic chemistry, cellular biology, and molecular biology.


Thiele, Todd
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Publications
PHD PROGRAM
Neurobiology

My primary research interests are directed at the neurobiology of alcoholism. To study the central mechanisms involved with neurobiological responses to ethanol, I use both genetic and pharmacological manipulations. There are many factors that may cause an individual to progress from a moderate or social drinker to an alcoholic. In addition to environmental influences, there is growing evidence in both the human and animal literature that genetic factors contribute to alcohol abuse. Furthermore, the risk for developing alcoholism is likely not associated with a single gene, but rather with multiple genes that interact with environmental factors to determine susceptibility for uncontrolled drinking. Some of the questions that my laboratory is currently addressing are: 1) Does central neuropeptide Y (NPY) signaling modulate neurobiological responses to ethanol and ethanol consumption, 2) Do melanocortin peptides modulate ethanol intake? and 3) Does cAMP-dependent kinase (PKA) play a role in voluntary ethanol consumption and/or other effects produced by ethanol?


Thompson, Nancy
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Publications
PHD PROGRAM
Chemistry
RESEARCH INTEREST
Biophysics, Cell Biology, Immunology

The immune system is a network of interacting biological cells. The molecular events that lead to the activation and regulation of these cells often occur at the cell surface. However, little is known about the arrangement, motions and interactions of the participating cell-surface molecules. To examine these phenomena, we construct model cell membranes on planar supports from purified or synthesized molecules.  Recently developed techniques in laser-based fluorescence microscopy can then be employed to examine the behavior of select fluorescently labeled molecules at or near the supported planar membranes.  This research is significant not only in the basic understanding of the immune system, but also in other areas of cell-cell communication and cell membrane biophysics, in the physics of two-dimensional fluids, and in biotechnology.


Topics include gene discovery, genomics/proteomics, gene transcription, signal transduction, molecular immunology.  Disease relevant issues include infectious diseases, autoimmune and demyelinating disorders, cancer chemotherapy, gene linkage.


Projects involve the study of cellular and molecular events involved in autoimmunity, and development and application of genetic vaccines to prevent and treat autoimmunity and cancer.


Research in my laboratory focuses on the cardiovascular effects of air pollution and other environmental pollutants in human, animal, and in vitro models, as well as the dietary interventional strategies to mitigate the adverse health effects of air pollution exposure. We are currently conducting two clinical studies to investigate the cardiopulmonary effects of air pollution exposure, and to determine whether dietary omega-3 fatty acids can mitigate the air pollution-induced health effects in human volunteers. These studies provide good training opportunities for students who are interested in training in clinical and translational toxicology research.


Dr. Troester’s research focuses on stromal-epithelial interactions, genomics of normal breast tissue, breast cancer microenvironment, and molecular pathology of breast cancer progression. She is a Co-Investigator on the Carolina Breast Cancer Study (CBCS), a resource including breast tumors from thousands of African American women, and she is PI of the Normal Breast Study (NBS), a unique biospecimen resource of normal tissue from women undergoing breast surgery at UNC Hospitals. Dr. Troester has extensive experience in integrating multiple high dimensional data types. She is chair of the Normal Breast Committee for the Cancer Genome Atlas Project where she is leading coordination of histology, copy number, mutation, methylation, mRNA and microRNA expression data. She has more than a decade of experience working with genomic data and molecular biology of breast cancer progression and has published many papers in the area of breast cancer subtypes, breast microenvironment, and stromal-epithelial interactions. She has trained four postdocs, 12 predoctoral students and several undergraduates.


The major area of our research is Biomolecular Informatics, which implies understanding relationships between molecular structures (organic or macromolecular) and their properties (activity or function). We are interested in building validated and predictive quantitative models that relate molecular structure and its biological function using statistical and machine learning approaches. We exploit these models to make verifiable predictions about putative function of untested molecules.


We aim to dissect the epigenetic and transcriptional mechanisms that shape T cell lineage specification during development in the thymus and in the periphery upon antigen (microbial, viral) encounter. Aberrant expression of transcription and epigenetic factors can result in inflammation, autoimmunity or cancer. We are using gene deficient mouse models, multiparameter Flow Cytometry, molecular biology assays and next generation sequencing technologies to elucidate the regulatory information in cells of interest (transcriptome, epigenome, transcription factor occupancy).


We are a quantitative genetics lab interested the relationship between genes and complex disease. Most of our work focuses on developing statistical and computational techniques for the design and analysis of genetic experiments in animal models. This includes, for example: Bayesian hierarchical modeling of gene by drug effects in crosses of inbred mouse strains; statistical methods for identifying quantitative trait loci (QTL) in a variety of experimental mouse populations (including the Collaborative Cross); computational methods for optimal design of studies on parent of origin effects; modeling of diet by gene by parentage interactions that affecting psychiatric disease; detection and estimation of genetic effects on phenotypic variability. For more information, visit the lab website.


Our broad long-term goal is to understand how mammalian cells maintain ordered control of DNA replication during normal passage through an unperturbed cell cycle, and in response to genotoxins (DNA-damaging agents).  DNA synthesis is a fundamental process for normal growth and development and accurate replication of DNA is crucial for maintenance of genomic stability.  Many cancers display defects in regulation of DNA synthesis and it is important to understand the molecular basis for aberrant DNA replication in tumors.  Moreover, since many chemotherapies specifically target cells in S-phase, a more detailed understanding of DNA replication could allow the rational design of novel cancer therapeutics.  Our lab focuses on three main aspects of DNA replication control:  (1) The S-phase checkpoint, (2) Trans-Lesion Synthesis (TLS) and (3) Re-replication.


We are interested in understanding how autoreactive B cells become re-activated to secrete autoantibodies that lead to autoimmune disease.  Our research is focused on understanding how signal transduction through the B cell antigen receptor (BCR) and Toll Like Receptors (TLR) lead to secretion of autoantibodies in Systemic Lupus Erythematosus (SLE).


Our lab uses computational and molecular tools to study the evolution of genome organization, primarily in the flowering plants. Areas of
investigation include the origin and consequences of differences in gene order within populations and between species, the evolutionary and functional diversification of gene families (phytome.org), and the application of genomics to evolutionary model organisms (mimulusevolution.org).  We also are involved in a number of cyberinfrastructure initiatives through the National Evolutionary Synthesis Center (nescent.org), including work on digital scientific libraries (datadryad.org), open bioinformatic software development (e.g. gmod.org) and the application of semantic web technologies to biological data integration (phenoscape.org).


Voruganti, Saroja
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Publications
PHD PROGRAM
Nutrition

My research interests are focused on understanding the effects of genetic and environmental factors and their interaction on complex human diseases using a combination of statistical, molecular and bioinformatics approaches. My specific interests include understanding the influence of genetic variants on serum uric acid levels (a biomarker for renal-cardiovascular disease), effect of gene by diet interactions on serum uric acid levels and associated renal-cardiovascular disease risk factors and identification of functional variants affecting these disorders that will lead to novel treatment options.


We are a molecular genetics laboratory studying immune functions by using mouse models. The focus of our research is to investigate the molecular mechanisms of immune responses under normal and pathological conditions. Our goal is to find therapies for various human immune disorders, such as autoimmunity (type 1 diabetes and multiple sclerosis), tumor and cancer, and inflammatory diseases (inflammatory bowel disease, asthma and arthritis).


With an emphasis on chromatin biology and cancer epigenetics, our group focuses on mechanistic understandings of how chemical modifications of chromatin define distinct patterns of human genome, control gene expression, and regulate cell proliferation versus differentiation during development, and how their deregulations lead to oncogenesis. Multiple on-going projects employ modern biological technologies to: 1) biochemically isolate and characterize novel factors that bind to histone methylation on chromatin, 2) examine the role of epigenetic factors (chromatin-modifying enzymes and chromatin-associated factors) during development and tumorigenesis using mouse knockout models, 3) analyze epigenomic and transcriptome alternation in cancer versus normal cells utilizing next-generation sequencing technologies, 4) identify novel oncogenic or tumor suppressor genes associated with leukemia and lymphoma using shRNA library-based screening. We are also working together with UNC Center of Drug Discovery to develop small-molecule inhibitors for chromatin-associated factors as novel targeted cancer therapies.


My laboratory has two research directions. One is to utilize nanotechnology to develop novel diagnostics and therapeutics to improve cancer treatment. The other is to use techniques developed in tissue engineering to develop in vitro 3D models of cancer metastasis.


We are actively engaged in multiple research arenas centered around understanding the associations between environmental exposures (primarily air pollution) and health outcomes. We use large clinical cohorts and electronic health records to understand associations between air pollution and health outcomes such as cardiovascular disease, metabolic disease, and aging. We use metabolomics and epigenetic data (primarily DNA methylation) to investigate molecular mechanisms, and highlight the integration of ‘omics data in a systems biology framework to better understand dysregulated pathways. Finally, we have projects centered around methods development and causal analyses to improve our understanding of the biology central to environmental health effects.


Waters, Marcey
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Publications
PHD PROGRAM
Chemistry

Our research focuses on several different aspects of biomolecular recognition, including (1) protein post-translational modifications, (2) protein-nucleic acid interactions, and (3) protein-protein interactions that are important in a number of different biological areas, including epigenetics and cancer.  We use bio-organic chemistry combined with peptide design and biophysical chemistry to study these interactions and to develop new tools for inhibition and/or sensing of these biomolecular interactions.


Watkins, Paul
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Publications
PHD PROGRAM
Toxicology
RESEARCH INTEREST
Physiology, Toxicology

Mechanistic toxicology, hepato-toxicology, research translation, biomarkers


Webster-Cyriaque, Jennifer
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Publications

A goal of the laboratory is to understand viral molecular pathogenesis in the oral cavity. We seek to understand the critical molecular interactions that occur between DNA viruses and the host that govern the development of oral disease.


The Weeks group invents novel chemical microscopes for understanding the structure and function of RNA and then applies these technologies to leading, and previously intractable, problems in biology. Most projects in the laboratory span fundamental chemistry or technology development and ultimately lead to practical applications in virology (especially HIV), next-generation structure analysis, drug design, and understanding RNA structure in living cells.  Collectively, this work has led to extensive recognition of graduate student colleagues in the laboratory.


I’m a neurobiologist who uses immunocytochemistry and electron microscopy to address functional questions. I am trying to elucidate the molecular organization of synaptic signaling in the rodent neocortex, hippocampus, and striatum. I’m also interested in the actin cytoskeleton of dendritic spines, and how spines may remodel during LTP.


The vertebrate retina is an extension of the central nervous system that controls visual signaling and circadian rhythm.  Our laboratory is interested in how the retina adapts to changing light intensities in the natural environment.  We are presently studying the regulation of 2 G protein-coupled receptor kinases, GRK1 and GRK7, that participate in signal termination in the light-detecting cells of the retina, the rods and cones.  Signal termination helps these cells recover from light exposure and adapt to continually changing light intensities.  Recently, we determined that GRK1 and GRK7 are phosphorylated by cAMP-dependent protein kinase (PKA).  Since cAMP levels are regulated by light in the retina, phosphorylation by PKA may be important in recovery and adaptation.  Biochemical and molecular approaches are used in 2 model organisms, mouse and zebrafish, to address the role of PKA in retina function. Keywords:  cAMP, cone, G protein-coupled receptor, GPCR, GRK, kinase, neurobiology, opsin, PKA, retina, rhodopsin rod, second messenger, signal transduction, vision.


How the loss of different components of the SWI/SNF complex contributes to neoplastic transformation remains an open and important question. My laboratory concentrates on addressing this question by the combined use of biological, biochemical and mouse models for SWI/SNF complex function.


My laboratory is interested in characterizing the role of cytoplasmic signal transduction pathways in regulation of androgen receptor activity and progression of prostate cancer.  Our studies have focused on HER-2 receptor tyrosine kinase and we have demonstrated that HER-2 activation stimulates androgen receptor activity and HER-2 inhibition inhibits androgen receptor transcriptional function at the level of recruitment to the androgen responsive enhancers.  These findings have led to the design and initiation of the protocol involving lapatinib, a clinical HER-2 inhibitor, in treatment of patients with prostate cancer.  More recently, we have demonstrated that activated Cdc42-associated kinase Ack1 promotes progression of prostate cancer via tyrosine phosphorylation of androgen receptor at Tyr-267 and Tyr-363 residues.  We are interested in further characterizing the role of tyrosine phosphorylation of androgen receptor in prostate cancer and development of Ack1 targeted therapy for clinical use.


White, Peter
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Publications
PHD PROGRAM
Biology

My research interests are wide ranging, including topics in conservation biology and plant ecology.  I have had several foci: species richness (including the All Taxa Biodiversity Inventory in Great Smoky Mountains National Park, beta diversity (including the comparison of diversity in different parts of the world that have similar climates and the connections to coinservation planning),and  the ecology of natural disturbances (including connections to environmental ethics and conservation of biodiversity).  Through my role as Director of the University’s North Carolina Botanical Garden, a conservation focused garden, I am also involved in research and poliy in invasive species biology, ecological restoration, ex situ conservation and reintroduction of rare species, and related subjects.


Whitehurst, Angelique
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Publications
PHD PROGRAM
Pharmacology

Our laboratory is interested in understanding the molecular machinery that drives tumorigenesis at the cancer cell autonomous level. In particular, we are interested in genes that support chemoresistance and/or mitosis in tumor cells.   We integrate data from high-throughput screening, cell biological, biochemical, translational and systems level approaches to identify and characterize genes that are involved in cancer cell survival and proliferation.


The Whitmire lab investigates how the adaptive immune system protects against virus infection.  The research is focused on understanding the mechanisms by which interferons, cytokines, and other accessory molecules regulate T cell numbers and functions following acute and chronic virus infections.  The goal is to identify and characterize the processes that differentiate memory T cells in vivo. The long-term objective is to develop strategies that improve vaccines against infectious diseases by manipulating these pathways.


Neurochemistry of dopamine, dopamine and behavior, exocytosis from single cells.


The Wilhelmsen lab is engaged in the genetic mapping of susceptibility loci for complex neurological diseases and has been developing large-scale automated gene mapping technologies to facilitate these mapping efforts. They have invested heavily in automation that enables high-throughput genotyping and data processing. As data accumulates, this will enable parametric and nonparametric linkage analysis of large numbers of traits at regular intervals for the entire genome. The Wilhelmsen lab is applying these techniques to two projects: (1) the genetics of alcoholism and (2) positional cloning of the gene responsible for a family of disorders called frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).


Willett, Christopher
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Publications
PHD PROGRAM
Biology

My lab concentrates on studying the molecular genetic basis of the evolutionary processes of adaptation and speciation. The questions we ask are what are the sequence changes that lead to variation between species and diversity within species, and what can these changes tell us about the processes that lead to their evolution. We use a number of different techniques to answer these questions, including molecular biology, sequence analyses (i.e. population genetics and molecular evolution techniques), physiological studies, and examinations of whole-organism fitness. Currently work in the lab has focused on a intertidal copepod species that is an excellent model for the initial stages of speciation (and also provides opportunities to study how populations of this species adapt to their physical environment).


Reproductive biology of early mammalian embryogenesis including gametogenesis, fertilization, and preimplantation embryo development. Effects of environmental disrupting chemicals on female reproductive tract development and function, with a focus on epigenetic alterations.


The overall objective of our research is to understand the connection between structure of protein-DNA complexes, protein dynamics and function.  We currently focus on the methyl-cytosine binding domain (MBD) family of DNA binding proteins.  The MBD proteins selectively recognize methylated CpG dinucleotides and regulate gene expression critical for both normal development and carcinogenesis.  We use a combination of NMR spectroscopy and biophysical analyses to study protein-DNA and protein-protein complexes involving the MBD proteins.  Building on these studies, we are developing inhibitors of complex formation as potential molecular therapeutics for b-hemoglobinopathies and cancer.


Divisions and decisions in development and disease. The mammalian skin epithelium is an ideal model system to study fundamental questions in stem cell and cancer biology. It is accessible; it can be cultured, genetically manipulated and transplanted; and its resident stem cells possess unparalleled regenerative capacity. Our skin, unlike many other organs, undergoes continuous growth and turnover. In development and homeostasis, progenitors in the skin must balance self-renewal and differentiation programs. We have found that asymmetric cell divisions are a critical mechanism by which skin progenitors maintain this equilibrium. We are interested in studying how this asymmetry is controlled at a molecular level, and how division orientation impacts cell fate choices in normal and neoplastic growth. To facilitate these and other studies in diverse epithelia, we have developed a powerful functional tool, lentiviral in vivo RNAi, which allows us to rapidly perform functional studies on any gene in the intact mouse in weeks instead of years. Our broad goal will be to use this technique, in combinations of candidate and screening approaches, to dissect pathways that influence stem cell differentiation. I will be joining the Pathology Department in April, 2013 and am seeking passionate, open-minded, and interactive students for the summer and beyond.


We investigate cellular, molecular, and biochemical mechanisms of blood coagulation.  Using in vitro, ex vivo, and in vivo models, we focus on mechanisms contributing to cardiovascular disease (heart attack, stroke, deep vein thrombosis), including the effects of plasma proteins, cells, and blood flow (shear) on blood clot biochemical and mechanical stability.  We have shown that abnormalities in blood protein and/or cellular function contribute to bleeding and clotting pathologies including hemophilia and thrombosis, and shown how hemostatic and antithrombotic therapeutics modulate clot quality.  Current efforts are focused on pathophysiologic mechanisms that result in bleeding or prothrombotic disease (e.g., cancer).  Our overall goal is to translate this knowledge into novel approaches for treating bleeding and clotting disorders.


Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen responsible for a variety of diseases in individuals with compromised immune function. Dr. Wolfgang’s research focuses on the pathogenesis of Pseudomonas aeruginosa infection.  The goal of his research is to understand how this opportunistic pathogen coordinates the expression of virulence factors in response to the host environment. Projects in his laboratory focus on the regulation of intracellular cyclic AMP, a second messenger signaling molecule that regulates P. aeruginosa virulence. Dr. Wolfgang’s laboratory uses a combination of molecular genetics and biochemical approaches to understand how P. aeruginosa controls the synthesis, degradation and transport of cAMP in response to extracellular cues. Other related projects focus on the regulation and function of P. aeruginosa Type IV pili (TFP). TFP are cAMP regulated surface organelles that are critical for bacterial colonization of human mucosal tissue. In addition, the Wolfgang lab is actively involved in characterizing the lung microbiome of patients with chronic airway diseases and studying the interactions between P. aeruginosa and other bacterial species during mixed infections.


We try to bridge the gap between genetic risk factors for psychiatric illnesses and neurobiological mechanisms by decoding the regulatory relationships of the non-coding genome. In particular, we implement Hi-C, a genome-wide chromosome conformation capture technique to identify the folding principle of the genome in human brain. We then leverage this information to identify the functional impacts of the common variants associated with neuropsychiatric disorders.


Our group develops novel statistical bioinformatics tools and applies them in biomedical research to help understanding the precision medicine for cancer (e.g., breast cancer and lung cancer) subtypes, the disease associated integrative pathways across multiple genomic regulatory levels, and the genetics based drug repurposing mechanisms. Our recent focus includes pathway analysis, microbiome data analysis, data integration and electronica medical records (EMR). Our application fields include cancer, stem cell, autoimmune disease and oral biology. In the past, we have developed gene set testing methods with high citations, in the empirical Bayesian framework, to take care of small complex design and genewise correlation structure. These have been widely used in the microarray and RNAseq based gene expression analysis. Contamination detection for data analysis for Target DNA sequencing is work in progress. Recently, we also work on single cell sequencing data for pathway analysis with the local collaborators.


Using genetic, cell biology, biochemical and proteomic approaches to determine the function and mechanism of – (1) CDK inhibitors in development and tumor suppression, (2) the p53 degradation and transport, and (3) RING family of ubiquitin ligases.


Yeh, Elaine
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PHD PROGRAM
Biology

The site of microtubule attachment to the chromosome is the kinetochore, a complex of over 60 proteins assembled at a specific site on the chromosome, the centromere. Almost every kinetochore protein identified in yeast is conserved through humans and the organization of the kinetochore in yeast may serve as the fundamental unit of attachment. More recently we have become interested in the role of two different classes of ATP binding proteins, cohesions (Smc3, Scc1) and chromatin remodeling factors (Cac1, Hir1, Rdh54) in the structural organization of the kinetochore and their contribution to the fidelity of chromosome segregation.


We are a translational research lab. The overall goal of our research is to find therapeutic targets and biomarkers for patients with pancreatic and colorectal cancer and to translate this to the clinic. In order to accomplish this, we analyze patient tumors using microarray analysis, identify and validate targets using forward and reverse genetic approaches in both cell lines and mouse models. At the same time, we evaluate novel therapeutics for promising targets in mouse models in order to better predict clinical response in humans. We also collaborate with the DeSimone and Huang labs to apply nanotechnology to drug delivery and therapeutics. Keywords: genomics, biomarkers, translational research, microarray, signaling, pancreatic cancer, colon cancer, mouse models, GEMM, drug discovery, nanoparticles.


Our laboratory is focusing on developing and applying solution-state NMR methods, together with computational and biochemical approaches, to understand the molecular basis of nucleic acid functions that range from enzymatic catalysis to gene regulation. In particular, we aim to visualize, with atomic resolution, the entire dynamic processes of ribozyme catalysis, riboswitch-based gene regulation, and co-transciptional folding of mRNA. The principles deduced from these studies will provide atomic basis for rational manipulation of RNA catalysis and folding, and for de novo design of small molecules that target specific RNA signals. Research program in the laboratory provides diverse training opportunities in areas of spectroscopy, biophysics, structural biology, computational modeling, and biochemistry.


Our lab studies lipid signaling pathways that are involved in development and diseases by developing novel chemical probes and technologies. As key components of cellular membranes, lipids also serve as signaling molecules and modify functions of proteins through either covalent or non-covalent interactions. Dys-regulation of lipid signaling has been correlated with various diseases including cancer, diabetes, and neurodegenerative diseases. Consequently, many lipid-related proteins or processes have been used as therapeutic targets. However, lipids are dynamically metabolized and transported, making it difficult to illustrate the roles of lipids in development and diseases with limited availability of probes and technologies for lipid studies. The active projects in the lab include: 1) develop novel technologies to synthesize complex lipids, particularly phosphatidylinositides, and identify their interacting proteins in live cells; 2) develop new small molecule sensors and inhibitors for lipid metabolic enzymes such as PI3K and PLC; and 3) investigate cellular functions of lipids on different processes, particularly those regulated by small GTPases.


We employ modern technologies – genomics, proteomics, mouse models, multi-color digital imaging, etc. to study cancer mechanisms. We have made major contributions to our understanding of the tumor suppressor ARF and p53 and the oncoprotein Mdm2.


The oxygen-sensing pathway contributes largely to the development of tumors. One of the central players in this pathway is prolyl hydroxylase (EglN1, 2 and 3). Our lab currently studies hypoxia signaling, prolyl hydroxylase and cancer, specifically breast and renal cell carcinoma. One project focuses on using proteomic and genomic approaches to screen for novel prolyl hydroxylase substrates that play important roles in cancer. The other project involves integrating CHIP-seq strategy with gene expression profiling in order to identify EglN2 prolyl hydroxylase and hypoxia inducible factor (HIF) targets in the malignant diseases. The ultimate goal is to understand mechanistically how oxygen-sensing pathways contribute to cancer progression, which will facilitate our design of efficient treatment strategies to specifically target cancer.


My research has been concentrated on the areas of statistical genetics and genomics to investigate the role of genetic variations on complex quantitative traits and diseases. I work primarily in the development, as well as the examination of statistical properties, of theoretical methodologies appropriate for the interpretation of genetic data.


Our research is focused on two general areas:  1. Autism and 2. Pain.  Our autism research is focused on topoisomerases and other transcriptional regulators that were recently linked to autism.  We use genome-wide approaches to better understand how these transcriptional regulators affect gene expression in developing and adult neurons (such as RNA-seq, ChIP-seq, Crispr/Cas9 for knocking out genes).  We also assess how synaptic function is affected, using calcium imaging and electrophysiology.   In addition, we are performing a large RNA-seq screen to identify chemicals and drugs that increase risk for autism.   /  / Our pain research is focused on lipid kinases that regulate pain signaling and sensitization.  This includes work with cultured dorsal root ganglia (DRG) neurons, molecular biology and behavioral models of chronic pain.  We also are working on drug discovery projects, with an eye towards developing new therapeutics for chronic pain.