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In my lab, we are exploring the roles that kinases play in neurodegeneration through the creation of high-quality, small molecule tools. Our team designs, synthesizes, and evaluates small molecules capable of kinase modulation, sometimes targeting kinase inhibition and sometimes kinase activation. In order to accomplish our aims, we work closely with X-ray crystallographers within the larger SGC and with biologists, including experts in using stem cells to model neurodegenerative diseases. We seek enthusiastic students with an interest in neuroscience who are willing to learn and apply techniques that span chemistry and biology to better understand and address neurodegeneration.


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.


The Drewry lab is focused on designing, synthesizing, evaluating, and sharing small molecule chemical probes for protein kinases. These tools are used to build a deeper understanding of disease pathways and facilitate identification of important targets for drug discovery. Through wide ranging partnerships with academic and industrial groups, the Drewry lab is building a Kinase Chemogenomic Set (KCGS) that is available to the community for screening.


We are inspired by the diversity and complexity found in natural products and use their architecture as both a platform for developing chemical methods and as scaffolds for new molecular tools in chemical biology. We have employed our chemical synthesis skill set to solve emerging challenges facing modern medicine. This has led to ongoing collaborative projects in metastatic cancer, hepatitis C antivirals, dopamine signaling and sigma receptor ligands. Of particular interest is the development of next generation anti-metastasis agents to our recent phase I clinical candidate, metarrestin.


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.


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.


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 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.


James, Lindsey Ingerman
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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.


Antiretroviral therapy (ART) is effective in suppressing HIV-1 replication in the periphery, however, it fails to eradicate HIV-1 reservoirs in patients. The main barrier for HIV cure is the latent HIV-1, hiding inside the immune cells where no or very low level of viral particles are made. This prevents our immune system to recognize the latent reservoirs to clear the infection. The main goal of my laboratory is to discover the molecular mechanisms how HIV-1 achieves its latent state and to translate our understanding of HIV latency into therapeutic intervention.

Several research programs are undertaking in my lab with a focus of epigenetic regulation of HIV latency, including molecular mechanisms of HIV replication and latency establishment, host-virus interaction, innate immune response to viral infection, and the role of microbiome in the gut health. Extensive in vitro HIV latency models, ex vivo patient latency models, and in vivo patient and rhesus macaque models of AIDS are carried out in my lab. Multiple tools are applied in our studies, including RNA-seq, proteomics, metabolomics, highly sensitive digital droplet PCR and tissue RNA/DNAscope, digital ELISA, and modern and traditional molecular biological and biochemical techniques. We are also very interested in how non-CD4 expression cells in the Central Nervous System (CNS) get infected by HIV-1, how the unique interaction among HIV-1, immune cells, vascular cells, and neuron cells contributes to the initial seeding of latent reservoirs in the CNS, and whether we can target the unique viral infection and latency signaling pathways to attack HIV reservoirs in CNS for a cure/remission of HIV-1 and HIV-associated neurocognitive disorders (HAND). We have developed multiple tools to attack HIV latency, including latency reversal agents for “Shock and Kill” strategy, such as histone deacetylase inhibitors and ingenol family compounds of protein kinase C agonists, and latency enforcing agents for deep silencing of latent HIV-1. Several clinical and pre-clinical studies are being tested to evaluate their potential to eradicate latent HIV reservoirs in vivo. We are actively recruiting postdocs, visiting scholars, and technicians. Rotation graduate students and undergraduate students are welcome to join my lab, located in the UNC HIV Cure Center, for these exciting HIV cure research projects.


Kratochvil, Huong
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PHD PROGRAM
Chemistry

We take inspiration from Nature to build new proteins that guide our understanding of how natural proteins function: we can distill complex natural proteins into simple model proteins where we have exact control over the physicochemical properties of the entire system. Our group combines protein design strategies with biochemistry, biophysics, and structural biology to 1) test mechanistic hypotheses of membrane protein structure and function, and 2) define novel protein-protein interactions in immunology for engineering protein-based therapeutics.


We focus on a variety of design goals including the creation of novel protein-protein interactions, protein structures, vaccine antigens and light activatable protein switches. Central to all of our projects is the Rosetta program for protein modeling. In collaboration with developers from a variety of universities, we are continually adding new features to Rosetta as well as testing it on new problems.


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.


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.


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 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.


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.


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.


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.


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.


We are interested in unraveling the molecular basis for human disease and discover new treatments focused on human and microbial targets. Our work extends from atomic-level studies using structural biology, through chemical biology efforts to identify new drugs, and into cellular, animal and clinical investigations. While we are currently focused on the gut microbiome, past work has examined how drugs are detected and degraded in humans, proteins designed to protect soldiers from chemical weapons, how antibiotic resistance spreads, and novel approaches to treat bacterial infections. The Redinbo Laboratory actively works to increase equity and inclusion in our lab, in science, and in the world. Our lab is centered around collaboration, open communication, and trust. We welcome and support anyone regardless of race, disability, gender identification, sexual orientation, age, financial background, or religion. We aim to: 1) Provide an inclusive, equitable, and encouraging work environment 2) Actively broaden representation in STEM to correct historical opportunity imbalances 3) Respect and support each individual’s needs, decisions, and career goals 4) Celebrate our differences and use them to discover new ways of thinking and to better our science and our community


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


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.


Waters, Marcey
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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.


One of the most amazing discoveries of recent years has been the profound role of RNA in regulating all areas of biology. Further, the functions of many RNA molecules require that an RNA fold back on itself to create intricately and complexly folded structures. Until recently, however, we had little idea of the broad contributions of RNA structure and function because there simply did not exist rigorous methods for understanding RNA molecules in cells and viruses. The vision of our laboratory is therefore, first, to invent novel chemical microscopes that reveal quantitative structure and function interrelationships for RNA and, second, to apply these RNA technologies to broadly important problems in biology. Mentoring and research in the lab are highly interdisciplinary. Students learn to integrate ideas and concepts spanning chemical and computational biology, and technology development, and extending to practical applications in virology, understanding biological processes in cells, and discovery of small molecule ligands targeted against medically important RNAs. Each student has a distinct project which they drive to an impactful conclusion, but do so as part of the lab team which, collectively, has shown an amazing ability to solve big problems in RNA biology. The overarching goal of mentoring in the lab is to prepare students for long-term leadership roles in science.


A unifying goal of my research is the use of chemistry as a tool to illuminate human biology. For over two decades I have led programs to develop potent cell active chemical probes to identify and study the biological function of their target proteins. Starting in 1992 with the orphan nuclear receptors, my lab developed chemical probes to uncover the roles of PPAR, PPAR, LXR, FXR, CAR, and PXR in human physiology. The release of our chemical probes into the public domain supported research across the global scientific community and resulted in multiple drug candidates to treat diseases of human metabolism entering clinical development. I am co-discoverer of the FXR agonist obeticholic acid, which was approved by the FDA in 2016 as a drug for the treatment of Primary Biliary Cholangitis.

In 2007, I started a collaboration with the Structural Genomics Consortium (SGC) to discover chemical probes for the enzymes and reader domains involved in epigenetic regulation. Together, we built a consortium with support from public funders and eight pharmaceutical companies that has released over 40 high quality chemical probes into the public domain. We demonstrated that the bromodomain family of acetyl lysine reader domains were highly tractable targets for drug discovery, which led to the development of BRD4 inhibitors for the treatment of various rare cancers.

In 2015, I established the first US site of the SGC at the University of North Carolina in Chapel Hill to expand the footprint of open science in US academia. I have assembled a team at SGC-UNC to create chemical tools for understudied (‘dark’) kinases, identify inhibitors of molecular targets that cause rare diseases, and develop chemical probes for proteins associated with neurodegenerative diseases. With support from the NIH Illuminating the Druggable Genome program we assembled a Kinase Chemogenomic Set (KCGS): the largest, highly annotated and publicly available collection of small molecule kinase inhibitors. We used KCGS to identify kinases whose inhibition prevents replication of coronaviruses including SARS-CoV-2. Medicinal chemists at the SGC-UNC are also developing chemical probes within the Med Chem Core of the NIA Target Enablement to Accelerate Therapy Development for Alzheimer’s Disease (TREAT-AD) program at UNC.


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.