The broad goal of our research is to understand basic mechanisms regulating erythropoiesis (red blood cell differentiation and maturation). Our current work focuses on a family of dual functional proteins (poly C binding proteins) which both regulate RNA processing and chaperone iron within cells. Using biochemical, cellular, and in vivo models we explore the cross talk between iron trafficking and RNA regulation mediated by poly C binding proteins and how these activities are modulated by disease.
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.
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 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.
How do networks of cells synchronize behaviors across differing spatial and temporal scales? This fundamental aspect of cellular dynamics is broadly relevant to understanding many biological systems in which the coherence of electrical or chemical signals is required for multicellular patterning or organ function. Our group’s primary research interests are related to understanding the cellular and microenvironmental conditions that are required to support the biorhythmic behavior of the system of cells that natively control heart rate, cardiac pacemaker cells. We utilize a variety of techniques including computational modeling, next generation sequencing, in vivo genetic manipulation, super-resolution imaging, and direct physiological recording to investigate the developmental processes that assemble the hearts pacemaking complex. The ultimate goals of these studies is to determine how the pacemaker cell lineage is patterned in the embryo, build strategies towards fabricating this cell type for therapeutic purposes, and identify vulnerabilities that may lead to pacemaker cell pathologies in humans.
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.
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.
Males and females differ in their prelevance, treatment, and survival to a diverse set of human disease states. This is exemplified cardiovascular disease, a disease that takes more lives than all forms of cancer combined. In cardiac disease, women almost uniformly fare far worse than men: as of 2007 one woman dying for cardiovascular disease in the US every minute. Our lab focuses on sex disparities in development and disease. For these studies, we use a highly integrated approach that incorporates developmental, genetic, proteomic, biochemical and molecular-based studies in mouse and stem cells. Recent advances by our past students (presently at Harvard, John Hopkins and NIH) include studies that define the cellular and molecular events that lead to cardiac septation, those that explore cardiac interaction networks as determinants of transcriptional specificity, the mechanism and function of cardiac transcriptional repression networks, and the regulatory networks of cardiac sexual dimorphism. Our lab has opening for rotation and PhDs to study these rapidly emerging topics.
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.
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.
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.
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.
Bioinformatics & Computational Biology
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.
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.
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.
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.
Our lab uses cell culture and animal models to define the mechanisms that lead to heart failure and to identify novel approaches to its treatment. We are particularly interested in the roles of inflammation and cardiomyocyte metabolism in the pathobiology of the failing heart. Ongoing projects focus on (1) the cardioprotective role of the alpha-1A adrenergic receptor; (2) transcriptional regulation by the nuclear receptor ROR-alpha; (3) cardiotoxicity of antineoplastic kinase inhibitors.
Endothelial cells, which comprise the innermost wall of all blood vessels, are involved in a broad range of metabolic and cardiovascular diseases that represent a global challenge with high morbidity. Endothelial cell metabolism is an active process, and altered endothelial metabolism drive disease progression. The research in my lab focuses on the molecular mechanisms of endothelial cell metabolism and how they affect cardiovascular and metabolic diseases.
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.
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.
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. 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.
Overall goal of our research is to gain better knowledge of gene-gene and gene-environment interactions in common cardiovascular conditions in humans. We have been modifying mouse genome in such a way that resulting mice can model quantitative variations of a specific gene product that occur in human population. With these mice, we explore causes, mechanisms, and nutritional treatments of cardiovascular complications resulted from common conditions such as diabetes, lung infections, and pregnancy-associated hypertension. Current focus is on the oxidative stress and effects of vitamin B12 as antioxidant and beyond.
Dr. McCullough’s lab takes a translational research approach that incorporates primary cell and organotypic in vitromodels with clinical research (controlled human exposures) to study the role of cellular and molecular mechanisms in mediating the local and systemic effects of exposure to inhaled chemicals. His laboratory utilizes primary cell/organotypic in vitro models, live cell imaging of fluorescent biosensors, and both traditional and advanced molecular biology/biochemistry methods to characterize the relationship between redox dysfunction/oxidative stress, inflammation, cell signaling pathway activation, epigenetic changes, gene expression, and cell-specific functional outcomes. In addition to identifying the mechanisms involved in the effects of toxic exposures, Dr. McCullough’s research also aims to identify biomarkers of toxic exposure effects, predicting susceptible populations, and identifying factors that can be used to mitigate adverse exposure outcomes.
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 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.
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.
The Polacheck Lab develops microfluidic and organ-on-chip technology for disease modeling and regenerative medicine. Our efforts are organized around three primary research thrusts: 1) Developing humanized microphysiological models for inherited and genetic disorders; 2) Defining the role of biofluid mechanics and hemodynamics on the cellular microenvironment; 3) Understanding the role of cell-cell adhesion in the generation and propagation of cellular forces during morphogenesis. We further work to translate the technology and techniques developed in our lab into tissue engineered therapies for organ replacement and regenerative medicine.
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.
Heart failure is an increasingly prevalent cause of death world-wide, but the genetic and epigenetic underpinnings of this disease remain poorly understood. Our laboratory is interested in combining in vitro, in vivo and computational techniques to identify novel markers and predictors of a failing heart. In particular, we leverage mouse populations to perform systems-level analyses with a focus on co-expression network modeling and DNA methylation, following up in primary cell culture and CRISPR-engineered mouse lines to validate our candidate genes and identify potential molecular mechanisms of disease progression and amelioration.
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 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.
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.
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.
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.
Our lab uses human genetics to identify new mechanisms driving coronary artery disease (CAD). Starting with findings from genome-wide association studies (GWAS) of CAD, we identify the causal gene at a given locus, study the effect of this gene on cellular and vessel wall biology, and finally determine the molecular pathways by which this gene influences CAD risk. Within this framework, we use complex genetic mouse models and human vascular samples, single-cell transcriptomics/epigenomics and high-throughput CRISPR perturbations, as well as traditional molecular biology techniques.
We investigate mechanisms in blood coagulation and diseases that intersect with abnormal blood biomarkers and function, including cardiovascular disease (heart attack, stroke, deep vein thrombosis, pulmonary embolism), bleeding (hemophilia), inflammation, obesity, and cancer. We also investigate established drugs and new drugs in preclinical development to understand their role in reducing and preventing disease. Our studies use interdisciplinary techniques, including in vitro, ex vivo, and in vivo mouse models and samples from humans in translational studies that span clinic to bench. Our lab emphasizes a culture of diversity, responsibility, independence and collaboration, and shared excitement for scientific discovery. We are located in the UNC Blood Research Center in the newly-renovated Mary Ellen Jones building.