Tight junctions are intercellular contacts that form a barrier required for ion transport and organization of cell polarity. Our lab investigates assembly and regulation of TJ proteins and the molecular basis for ion selectivity in epithelia.
We study arterioles that vascular resistance in healthy kidneys and kidneys of genetic hypertensive animals or those with mutated selected genes. Measurements include renal vascular reactivity in vivo and receptor/calcium signaling in vitro.
Research interests include atherosclerosis, thrombosis and von Willebrand's disease. The role of von Willebrand factor in arterial thrombosis is being studied in atherosclerotic vessels to gain a better understanding of thrombosis and its possible prevention in people with coronary artery disease. Comparative pathology and the use of animal models in research are also the focus of some research efforts.
I am collaborating with Dr. Rosann Farber on molecular mechanisms of microsatellite instability. Microsatellites are repetitive DNA sequences in which the number of bases in a repeat unit can number from 1-6 bases. Microsatellites are widely dispersed throughout the eukaryotic genome and there are differences in the numbers of repeats among alleles. These sequences are exceptionally unstable in cells lacking mismatch repair. We have developed a selective system in which to measure mutation rates in microsatellites in cultured cells. Using this system we can compare mutation rates and mutation spectra in normal and neoplastic cells and cells with or without mismatch repair. Much of our research has focused on the properties of microsatellites that may affect their mutation rate. These include: 1) length of the repeat unit (e.g., mono- vs. dinucleotides), 2) base composition of the repeat, 3) number of repeat units per tract, 4) degree of perfection of repeats (i.e., presence or absence of interruptions in the tract), and 5) composition of flanking sequences.
It has been postulated for some time that cellular transplantation to the liver might allow for the reversal of hepatic based genetic defects or augmentation of hepatocellular function. However, the identification of the proper cell type and transplant conditions to produce liver engraftment and normal hepatocyte function has remained elusive. We have developed an alternative strategy using embryonic stem (ES) cells differentiated /in vitro/ and transplanted into hepatic parenchyma as “gene vectors” in order to restore wild type hepatocellular function.
This laboratory has worked for over 25 years investigating both fundamental and clinically relevant aspects of ciliary and flagellar motility in eukaryotic cells. Our primary focus has been the elucidation of the processes surrounding differentiation, function, and injury of mammalian airway ciliated epithelial cells and how these cells respond to challenge by infectious agents, environmental irritants including tobacco smoke, and pharmacologic agents. Our laboratory is also part of a large national center for diagnosis, research, and treatment of Primary Ciliary Dyskinesia, a genetic disease affecting mucociliary clearance of the airways. This laboratory is designed around facilitating light and electron microscopic
analyses but collaborates closely with other laboratories and colleagues working on cell and molecular biology topics in airway epithelial cell biology.
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 research is concerned with proteases and their inhibitors in various disease processes (thrombosis and cancer); our science tools are structure-activity, cell biology and signaling, pathobiology, immunohistochemistry, and in vivo models.
The major interest of this laboratory is the differentiation and regulation of autoreactive B cells in health and disease. Our long-range goal is to identify and understand the mechanisms that regulate autoreactive B cells and how they fail in disease. Such information is key to devise rational new therapeutic strategies for the treatment of autoimmune diseases such as systemic lupus erythematosus (SLE). The lab currently has three main research focuses: 1) regulation of B cells specific for the ribonucleoprotein antigen Sm, a target of the immune system in SLE, 2) analysis of how Epstein Barr virus (EBV) contributes to SLE and 3) investigation of activation of anti-Sm B cells in blood of human SLE patients.
Cross-talk between insulin like growth factor -1 and cell adhesion receptors in the regulation of cardiovascular diseases and complications associated with diabetes
The research in our laboratory involves several major projects related to the molecular pathogenesis of human cancer and investigations related to the biology of liver stem-like progenitor cells, including (i) characterization of human liver tumor suppressor genes, (ii) analysis of genetic determinants of breast cancer, (iii) investigation of mechanisms governing aberrant DNA methylation in breast cancer, (iv) liver progenitor cell responses after toxic liver injury, and (v) transplantation of liver stem-like progenitor cells for correction of genetic liver disease.
Diabetes and insulin resistance: lipid and carbohydrate metabolism; obesity: partition of energy between triacylglycerol storage and fatty acid oxidation; regulation of triacylglycerol synthesis; hepatic steatosis
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.
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).
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.
Genetic instability in cultured human cells and yeast, microsatellite mutations, DNA mismatch repair, hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome), human genetics, somatic-cell genetics.
The research program of Dr. Fischer focuses on three closely related areas. Mechanisms for atherogensis, processes of platelet-mediated hemostasis and mechanisms for surface hemostasis.
The central goal of my research is to understand how immune cells are activated and regulated within the Central Nervous System. Our research looks at the different pathways of activation of the microglia, the role of the microglia in sensory responses, and the role of stress responses in activating and regulating the response of the microglia. We are currently investigating the mechanism of microglia activation and regulation in Parkinson's Disease (PD). We also study the mechanisms by which CD8 T lymphocytes dictate the nature of inflammatory responses to cancer cells. Research in my laboratory seeks to delineate the immunologic mechanisms involved in the generation of protective anti-tumor responses in CD8 cell populations, and in developing therapies for treatment of cancer.
Dr. Gulley's research is on Epstein-Barr virus (EBV)-related malignancies. Molecular and immunohistochemical techniques are used to characterize infected tissues. We validate new assays to help diagnose and monitor affected patients.
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 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).
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.
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.
Research in the Kaufmann laboratory is concerned with determining the mechanisms whereby cell cycle checkpoints suppress human cancer development. We are focused on two checkpoints that help to stabilize the genome. The decatenation G2 checkpoint delays mitosis until daughter chromatids are sufficiently disentangled by topoisomerase II. This checkpoint is regulated by the breast cancer susceptibility gene BRCA1. The intra-S checkpoint regulates DNA synthesis by controlling the rates of replicon initiation and DNA chain elongation. This checkpoint is regulated by two proteins, Timeless and Tipin, that mediate signaling at stalled replication forks. A program project is studying how the Timeless-Tipin replication fork protection complex protects against UV-induced chromosomal damage and sunlight-induced melanoma.
Our focus is on using genetic methods to improve transplantation using ES and hematopoietic stem cells in transplant models. A second focus of the lab uses mutant mice to examine potential drug targets for ameliorating radiation-induced lung damage.
We have used gene targeting to generate an animal model for the most common genetic disease in the Caucasian population, cystic fibrosis. We are continuing to characterize this animal and to modify it to produce a disease that more closely resembles human cystic fibrosis. A second area in which our lab is interested involves the study of the inflammatory processes involved in allergic responses, asthma, and arthritis. Our current efforts are aimed at generating animals deficient in various factors that are believed to be important in these diseases. By providing us with a better understanding of the immunological processes that underlie allergic responses, asthma and arthritis, these animals should help us to identify more effective treatments for these diseases.
I study a canine model of Duchenne muscular dystrophy. Both conditions occur due to mutations in the dystrophin gene. Our research has defined clinical and pathologic features to better understand disease pathogenesis and to assess treatment.
We study the blood clotting protein fibrinogen, its biochemistry and its role in disease (Curr Opin Hematol. 14:236, 2007). We synthesize variant fibrinogens to correlate structure and function using crystallographic and biochemical analyses (Biochemistry 46:5114, 2007). We examine the mechnical properties of fibrin fibers using atomic force microscopy (Science 313:634. 2006). We explore the interactions of fibrinogen with biomaterials (Acta Biomaterialia 3:663, 2007). We use patient samples and mouse models to examine the links between fibrinogen and disease (J Thromb Haemost. 2:1484, 2004). Member of the Molecular & Cellular Biophysics Training Program.
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.
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.
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 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
Our interest lies in the understanding of mechanisms involved in adaptation and restitution of function of striated muscle during development, injury and disease states. Regeneration of striated muscle including cardiac tissue and skeletal muscle is being actively sought with the use of various types of stem cells from various origin. We are investigating the mechanisms that control adult-derived stem cells to aquire a cardiac phenotype.
My research interests focus on molecular events involved in the initiation of autoimmune response in multiple sclerosis (MS) and mechanisms of action of immunomodulatory and neuroprotective therapies for this disabling disease.
Our laboratory is interested primarily in the responses of macrophages during injury to the central nervous system and during inflammation after insult by bacterial pathogens. We use molecular, cellular and biochemical approaches both in vitro and in vivo to identify the function of key mediators during pathogenesis.
My laboratory studies diffuse gliomas, devastating primary tumors of the central nervous system for which few effective drugs are currently available. We utilize model systems (genetically engineered mice, cultured cells, and human tumor specimens) to explore the molecular pathogenesis of
and develop drugs and diagnostic markers for individualized therapy of gliomas. Rotating students gain experience with techniques that include genomics (expression microarrays and array CGH), fluorescence microscopy, computer-enhanced image analysis, and tissue microarrays.
We are identifying genetic variants that influence common human traits with complex inheritance patterns, and we seek to understand the biological function of the identified variants. Currently we are investigating susceptibility to type 2 diabetes and obesity, as well as variation in cholesterol levels, blood pressure, body size, weight gain and early growth. 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, genetic epidemiology, resequencing, bioinformatic analysis, molecular biology, cell biology, and mouse models to compare high- and low-risk alleles in a whole-animal setting.
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.
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.
Dr. Preston's research interests address fundamental genetic and biochemical questions related to autoimmune diseases that affect the kidney. A recent discovery by Dr. Preston and coworkers led to the formulation of a novel theory that delineates potential "triggers" that lead to autoantibody production (Nature Medicine 10: 72-79, 2004). Dr. Preston works closely with the research team within the UNC Kidney Center,including the Director of the Center, Ronald Falk, MD. and the Clinical Core, which obtains biologic samples
from patients for research purposes. These interactions provide the perfect setting for a truly Translational Research Program within the UNC Kidney Center
My interests include the use of immunological and molecular probes to study function of normal and abnormal coagulation factors; the study of factors regulating human immune response to coagulation factors; and immunochemical studies of antigen-antibody interaction.
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.
Our laboratory is involved in studies to determine the mechanisms and proteins involved in the migration of alloreactive and regulatory T cells to organs involved in graft-versus-host disease after stem cell transplantation using mouse models.
Correction of genes with mutant pathologies (gene therapy); construction of animal models of human genetic diseases to facilitate better studies of the resultant pathology and develop new modes of treatment.
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.
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.
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.
Blood Flow and Endothelial Cell Function. We are interested in how vascular endothelial cells signal and respond to blood flow in the context of cardiovascular disease and tumor progression.
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.
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.
Construction of chimeric antithrombotic proteins targeted to endothelial cell surfaces; Activity of these using in vitro assays and in vivo mouse models of arterial and venous thrombosis; pathophysiology of hemostasis/thrombosis in these mouse models.
We investigate the role of cardiac specific proteins (Muscle Ring Finger or MuRF proteins) that regulate glucose and fatty acid metabolism, cardiac muscle mass, and sarcomere protein metabolism in the context of common cardiac diseases. Recently, we have identified that MuRF proteins have ubiquitin ligase activity, which enables them to interact with specific proteins, post-translationally modify them with ubiquitin, and subsequently target them for degradation. We focus on mouse models of disease using transgenic and knock-out mice, integrating cardiac physiology with several imaging modalities including echocardiography, Doppler, and SPECT. Since several of the models we have created involve developmental defects, we investigate in utero cardiac function and signaling pathways
with this state of the art of imaging. Our overall goal is to determine how the ubiquitin proteasome system specifically regulates the heart at the molecular level and determine how this affects cardiac function, in order to
translate these findings into therapies & diagnostics for common cardiac diseases such as heart failure and myocardial infarction.
Cellular, molecular, and biochemical mechanisms of blood coagulation; Relationships between cells (monocytes, fibroblasts, endothelial cells, smooth muscle cells, platelets and others), plasma protein concentration, thrombin generation and blood clots; Fibrin formation, structure and stability; Mechanical properties of fibrin; Disorders associated with bleeding and thrombosis, including hemophilia and cardiovascular disease (heart attack, stroke, deep vein thrombosis, pulmonary embolism); Preclinical testing of hemostatic and antithrombotic drugs
