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.
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?
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.
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.
We study the interface between signal transduction and cell function. Approaches employed include - molecular genetics, protein and lipid biochemistry, confocal and electron microscopy, protein crystallography, and model organisms approaches (e.g. yeast, Arabidopsis, C. elegans, mouse gene knockout technology).
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.
We study the cell biology of the protozoan parasites that cause Toxoplasmosis and Malaria, especially the mechanism and control of parasite motility and host cell interaction.
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.
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.
Cell adhesion, both to other cells and to ECM, signaling, the cytoskeleton and cell migration. The Rho family of GTPases, their regulation by guanine nucleotide exchange factors and GAPs. Inflammation and leukocyte transendothelial migration.
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.
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.
Our research centers on the cell biology and biochemistry of motor proteins and the cytoskeleton and their roles in processes such as cell crawling, phagocytosis, organelle transport.
Steroid hormones regulate tissue-specific gene expression in animals via receptor dependent intracellular signal transduction pathways. We are particularly interested in glucocorticoid receptors and their actions on the immune system because they reflect the primary response to environmental stress. Current research projects are examining the following aspects of glucocorticoid hormone action. A second major interest of the laboratory focuses on evaluating the mechanisms involved in the regulation of apoptosis in normal and neoplastic cells. Research is aimed at the identification and cloning of genes that are responsible for both the initiation and execution of apoptosis.
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.
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.
We study cell cycle control of DNA replication licensing, the process that renders replication origins competent to initiate DNA synthesis. We investigate how the replication process is linked to cell cycle progression and the signaling pathways that gather and transmit information about the cellular environment. Our experimental approach is to manipulate human cells in culture (both cancer cell lines and normal cells) through a variety of molecular and genetic strategies; some projects utilize budding yeast as a model system due to the sophisticated genetic tools available in that organism. We measure protein abundance and stability, chromatin localization and modifications, cell cycle progression, protein-protein interactions, and checkpoint functions. Our long-term goals are to understand the molecular events that ensure genome stability and how those events are disrupted in cancer cells.
Mechanisms of DNA replication, DNA repair, and cell cycle checkpoints are studied in cultured human cells and using biochemical assays in vitro. It includes translesion synthesis by DNA polymerase eta and its role in suppressing mutagenesis by solar radiation. Inherited and acquired defects in the network of protection of genetic stability are associated with increased risk for mutations underlying cancer pathogenesis. Current goals are to identify key molecular events in melanoma development associated with sun exposure. Other collaborative studies aim at localization of functional origins and characterization of DNA replication dynamics.
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 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.
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.
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 activate the programmed cell death pathway and die by apoptosis. We have focused our work on identifying unique mechanisms by which this pathway is regulated in postmitotic cells such as neurons, cardiomyocytes, and myotubes, as well as cancer, senescent, and stem cells. Excessive cell death is seen in many pathological conditions such as after stroke, neurodegeneration or cardiovascular diseases. In contrast, reduced cell death is a hallmark of cancers. Therefore, discovering the mechanism by which mammalian cells regulate cell death has significant therapeutic implications.
Our lab tries to understand viral pathogenesis. To do so, we work with two very different viruses - West Nile Virus (WNV) and Kaposis sarcoma-associated herpesvirus (KSHV/HHV-8).
The Dokholyan group focuses primarily on understanding protein dynamics, more specifically on how induced changes in protein folding and aggregation lead to diseases, such as cystic fibrosis, many types of cancers, and a number of neurodegenerative diseases. The Dokholyan group focuses on several such diseases, including Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrigs disease, and Huntington disease. The Dokholyan group is developing a hierarchy of molecular models, from simplified coarse-grained models to more detailed ones, to create a novel multi-scale simulation methodology. This methodology will enable simulations of large molecular complexes at the biologically-relevant time scales, thereby allowing to directly glance into processes associated with human diseases. Member of the Molecular & Cellular Biophysics Training Program.
My lab studies membrane traffic between the trans-Golgi network and endosomal organelles. This central feature of eukaryotic cell biology is important for functions of the human body; including the ability to recognize and destroy infective agents, sugar uptake in response to insulin and the proper reaction of cells to growth factors-a feature important in normal development and that is often inappropriately regulated in cancer. We have two main types of projects in the lab; characterizing protein-protein interactions important for membrane traffic and chemical genetic approach to identify compounds that regulate membrane traffic.
Mechanisms of cell cycle control by cyclin dependent kinases (CDK's) and gene expression during Drosophila development, including how transcription factors (the pRB tumor suppressor and E2F), RNA metabolism (histone pre-mRNA processing), and protein ubiquitination and proteolysis (cullin dependent ubiquitin ligases) regulate the G1-S transition and DNA replication.
Our lab is interested in how signals from membrane receptors are transduced to the nucleus altering gene expression, cell shape, proliferation and differentiation. We are particularly interested in tyrosine-specific protein kinases in breast and prostate cancer, as well as lymphoma/leukemia. Particular focus of the lab include:1) roles of the EGF receptor family and related molecules HER4/ErbB4 in growth inhibition and differentiation and 2) Mer (a novel receptor tyrosine kinase) and how signals downstream from Mer enhance prostate tumorigenesis.
We are characterizing the structural signals that are responsible for moving proteases normally stored intracellularly in lysosomes into the extracellular environment, where they may participate in tumor cell metastasis. One putative mediator of this altered protease targeting is an endosomal integral membrane protein that behaves like a cellular "dirty bomb", undergoing proteolysis which releases fragments that target to various cellular sites where they serve distinct functions. The multiple proteolytic cleavages ultimately release the cytoplasmic tail from the membrane. This tail, which possesses a putative signal for import into the nucleus, can modify other proteins with ubiquitin, which causes them to be degraded rapidly. Proteolysis of the putative receptor is mediated by the same enzymes that cleave the Alzheimer's precursor protein into fragments that can aggregate to form plaques in the brain. When neurite outgrowth is stimulated, expression of this protein is upregulated, suggesting that it also plays a role in development. We are using biochemical characterization of the protein's domain structure to relate its proteolysis, cellular targeting, and signaling to the nucleus to altered targeting of lysosomal enzymes.
Investigation of genes/proteins that play key roles during embryonic and postnatal development of craniofacial/oral/dental structures; and their contribution to normal variation and to congenital and acquired disorders.
This lab studies vascular biology and physiology, with specific focus on the signaling mechanisms directing 1) normal adaptive and pathological growth of the vascular wall, 2) arteriogenesis (formation of collateral vessels) in models of tissue ischemia.
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.
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.
We study intracellular trafficking of the chloride channel CFTR in heterologous systems and in primary human airway epithelial cultures. The most common mutation in cystic fibrosis, deltaF508, results in a misassembled protein that is retained at the ER but can escape and proceed to the plasma membrane by addition of small molecule correctors or low temperature incubation. Temperature-rescued deltaF508 disappears rapidly from the cells surface and is subjected to lysosomal degradation, while wild-type CFTR is recycled back to the plasma membrane. Of particular interest is the mechanism that leads to elimination of detlaF508 from the cell surface.
We are using C. elegans embryos to address fundamental issues such as how cells move to specific positions during embryonic morphogenesis, how the orientation of cell division is determined, how the mitotic spindle is positioned in cells and how cells respond to cell signaling. We use diverse methods, including methods of cell biology, developmental biology, forward and reverse genetics including RNA interference, biochemistry, molecular biology and live microscopy of cells and the cytoskeleton. We are also developing water bears as a
new model system to study the evolution of development.
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.
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.
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.
Our research focuses on determining the mechanisms responsible for craniofacial birth defects. We use the whole embryo culture system to expose mouse conceptuses to toxicants and evaluate morphological, molecular (Affy arrays) and protein changes. Antisense morpholinos and adenoviruses are used to modulate gene expression and determine phenotypic effects. We are using embryonic stem cells as a model to evaluate the effects of environmental chemicals on differentiation. Using molecular markers to identify differentiation may provide critical information to identify developmental toxicants.
Structure, dynamics and function of viral domains in biomembranes. Photomanipulation and traction mapping applied to the migration of single cells. Investigation of the mechanochemical basis of cell oscillations using systems biology approaches coupled with experiments.
We are studying how hemangioblasts, a bipotential precursor of endothelial and hematopoietic lineages, are specified and differentiated during development using zebrafish as a model system.
Signal transduction coupled by heterotrimeric G proteins. We use Arabidopsis, genetics, biochemistry, & in vivo imaging of protein-protein interactions. The type of signals we study include light, hormones, & sugars.
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.
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.
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.
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.
Lab research signals and effectors necessary to establish regional and cellular differences in the regions of the forebrain. Human diseases are a starting point for identifying novel genes that may participate in normal forebrain development.
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.
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
We study genetic controls of vascular development in mouse and chick models. Current projects focus on the roles of sonic hedgehog and transcriptional silencers in control of vascular stem and progenitor cell differentiation. Other ongoing projects examine the role of notch signaling in coronary artery development, and explore the link between cytoskeletal remodeling and transcriptional activation in smooth muscle differentiation.
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.
Research in our laboratory falls at the interface between Genetics and Cell Biology and is concentrated on understanding the molecular details of how small nuclear ribonucleoprotein (snRNP) complexes are assembled and transported to their proper subcellular compartments. Interestingly, defects in the machinery required for assembly of snRNPs are associated with a neurogenetic disease called Spinal Muscular Atrophy (SMA). Mutations in the human survival of motor neurons 1 (SMN1) gene cause SMA. A variety of projects in the lab are focused on SMN's role in the biogenesis of small RNPs as well as in neuromuscular development and function. Other projects focus on nucleocytoplasmic trafficking and the functional organization of the nucleus. We use a combination of approaches, from in vitro biochemistry and cell culture, to in vivo mouse and Drosophila model systems.
Dr. Meeker’s research is focused on the mechanisms of HIV neuropathogenesis. 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.
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.
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 adaptations; etiology of essential tremor.
My laboratory has two main interests: 1) P2Y receptor trafficking in epithelial cells. 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 role of lipid rafts and caveolae in P2Y receptor function. 2) Antibiotic resistance mechanisms. We are interested in 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 cephalosporin. We also study the biosynthesis of the gonococcal Type IV pilus and its contribution to antibiotic resistance.
Our lab investigates molecular and cellular mechanisms that regulate mammalian spermatogenesis and fertilization. A major focus of our current research is sperm energy metabolism. Our gene knockout studies demonstrate that glycolysis is essential for sperm motility and male fertility, and genomic analyses indicate that male germ cells express unique enzymes for nearly every step in this central metabolic pathway. These sperm-specific glycolytic enzymes have distinctive properties, as demonstrated by biochemical and structural analyses. Understanding how sperm energy production is regulated has significant therapeutic potential, both for the development of new contraceptive strategies and the clinical management of infertility.
Fertilization leads to the formation of a new diploid individual and represents an exquisite example of the specificity of cell to cell and cell surface-extracellular matrix interaction. Our research laboratory is interested in the study of the structure and function of sperm proteins. The long-term goal of our research is to define a set of sperm molecules that are necessary for one or more steps in the fertilization process. A full understanding of the mechanisms of sperm maturation and fertilization would allow precise targets for both infertility diagnosis and contraception.
Currently, the structure and function of two different proteins are under study. These proteins are: 1) NASP a nuclear protein that binds and transports linker histones into the nucleus and is critical for mitosis and meiosis; 2) Eppin a testis and epididymal serine protease inhibitor.
An important step in the development of tests for the diagnosis of infertility and for the development of a male gamete based contraceptive is the determination of specific protein-protein interactions that are necessary for fertilization. Characterization of these interactions will
provide sites for contraceptive development.
Mechanisms by which cells control their shape via modulation of the actin cytoskeleton. Palladin, a novel cytoskeletal protein, may be involved in organizing the actin cytoskeleton as a scaffolding protein and may contribute to changes in cell shape.
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.
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.
Using a combination of in vivo and in vitro approaches, our lab studies the extracellular cues and intracellular signaling pathways regulating neuronal migration, axon guidance and dendritic differentiation during early aspects of brain development.
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
Identification of airway epithelial stem cells; innate immunity in the airway; the pathophysiology of post-lung transplant ischemia reperfusion injury and bronchiolitis obliterans syndrome.
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.
The Chromosomal Stability Group integrates mechanisms and genetic controls of genome stability with environmental factors and stress responses to better understand their complex contributions to human health. Using budding yeast and human cell models, research focuses on genome maintenance and natural or environmental challenges to chromosome stability. Repair, replication and checkpoint functions are investigated to understand sources of genome instability and mechanisms of coping with DNA damage, particularly double-strand breaks. Included in these studies are the roles that human genes and networks, particularly p53, play in stress responses.
The primary research focus is the structure, function and biosynthetic processing of membrane proteins which provide permeability pathways through the membranes of cells. Much of the current work is concentrated on the ion channel protein, CFTR (cystic fibrosis transmembrane conductance regulator) which is absent or dysfunctional in patients with cystic fibrosis. To elucidate the molecular mechanisms of CFTR function, we study single channel properties by electrophysiological techniques, enzymatic activity and physical interaction with other cellular molecules. A major objective of studies with the purified molecule is to obtain 3-dimensional structure information so that small molecules capable of recognizing features of its surface shape can be synthesized and used to modulate its folding and activity.
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.
Bioinformatics, Cancer Biology, Cell Biology, Chemical Biology, Computational Biology, Genomics, Molecular Medicine, Neurobiology, Pharmacology, Systems Biology, Toxicology, Translational Medicine
Spindle microtubule, microtubule motor and kinetochore mechanics for accurate chromosome segregation. We are also developing new fluorescence microscopy and electronic imaging methods for assays of protein function in living cells.
Cell adhesion controls cellular functions implicated in human disease, e.g. cancer. FAK, a tyrosine kinase, is a major component of this signaling pathway. We study the function and molecular mechanisms by which FAK controls these events.
The lab relies on murine genetic approaches to study the roles of the INK4/ARF tumor suppressor locus in human cancer and aging. At present, the lab has two main focuses:
Stem Cell Aging:
Cancer and degenerative diseases are much more common in old people than young. Although this has been well-recognized in clinical medicine for decades, scientists do not agree as to why this occurs. Recently, work from several labs including our own has shown that humans age, in part, because important regenerative cells lose their capacity to divide with the passage of time. That is, the tissues and organs from old people are less able to replace and regenerate lost or damaged cells than the corresponding tissues and organs from young people. Our lab has studied mechanisms that underlie this age-dependent failure of cell division; in fact, we have shown the surprising result that cellular programs that function to prevent cancer untowardly also calls aging. Specifically, cellular “senescence” is now believed to be of major importance in the process of aging. Senescence refers to a permanent growth arrest induced in formerly dividing cells by the activation of genes that prevent cancer. The good news in this system is that the normal functioning of these ‘tumor suppressor genes’ prevents cancer; the bad news is that these same genetic events appear to cause aging by activating cellular senescence.
Melanoma and Murine Models of Cancer:
Because of the important role of p16INK4a in preventing melanoma, the lab has long been interested in this particularly deadly form of skin cancer. Specifically, we are interested in using genetically engineered models of cancer to study melanoma genetics. We have shown a role for the p16INK4a-RB and ARF-p53 tumor suppressor pathways in repressing this important human cancer in response to RAS-RAF activation. We have generated highly faithful models of human melanoma, and have used these to study novel therapeutics. We have also discovered a novel human melanoma sub-type based on expression profiling, and have identified a new therapeutic target (CD200) for treatment of melanoma.
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.
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.
Work in my laboratory is directed at the role of neuronal growth factors in the development and regeneration of axons. We employ sensory neurons of the DRG as a model system. Sensory neurons are unique in elaborating a peripheral axon that regenerates readily after injury and a central axon projecting in the spinal cord that does not. This work is directly relevant to a major NINDS goal of achieving spinal cord repair.
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.
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.
The mechanical properties, force response and force generating mechanisms of biological systems is of great interest for physiological function, for tissue engineering and embryogenesis and for drug delivery. In collaboration with the Computer Science Department, we develop and apply new technologies for applying and measuring forces on single molecules, cells and tissue cultures. In collaboration with the departments of Mathematics, Computer Science, Chemistry and the UCN Cystic Fibrosis Center we are pursuing an integrated computational model of mucus clearance in the lung. Affiliated with the Molecular & Cellular Biophysics Training Program.
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.
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 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.
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.
We study mechanisms of cancer using cutting edge technologies - genetically engineered mice, microscopy, genomics, cell culture and more. We have developed many models cancer and have made major contributions on the functions of p53, pRb and PTEN.
The genetic pathways for the development of cardiac and vascular smooth muscle cells. In particular, the transcriptional control of mammalian cardiovascular system, and cell proliferation and differentiation-related human cardiovascular disorders.
The laboratory is interested in the role of G proteins and G protein-coupled receptors in the regulation of mammalian cell metabolism, growth control and differentiation. Specific questions addressed by the lab include (1) What are the structural determinants of G-protein-coupled receptors that regulate their interactions with G proteins and with proteins such as kinases and arrestins that are involved in receptor desensitization? and (2) What roles exist for G protein-coupled pathways in the growth and differentiation of mammalian cells? Rhodopsin, the photoreceptor of the mammalian retinal rod, is used as a molecular model for defining the domains of G protein-coupled receptors responsible for the binding and activation of their specific G proteins. Experiments also focus on the mechanism of desensitization of this receptor by phosphorylation and arrestin binding.
Our work focuses on molecular aspects of androgen receptor regulation of gene expression, which includes coactivator interactions with the androgen receptor and its functional importance in various clinical syndromes.
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.
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 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.
Our lab is interested in how dynamic changes in chromatin structure affect gene expression, cell lineage determination and cancer development. Currently, we are focusing on two epigenetic modifications, DNA methylation and histone methylation.
We recently found that nociceptive (pain-sensing) circuits in mammals are highly organized at molecular and neuroanatomical levels. In our laboratory, we are using molecular, genetic, electrophysiological and behavioral approaches to study these pain circuits in mice. Our ultimate goal is to identify new analgesics so that debilitating chronic pain conditions can be more effectively treated.
Techniques used in our lab include: Molecular biology and cell culture; In situ hybridization and immunofluorescence staining; Construction and characterization of knock-in and transgenic mice; Mouse behavioral experiments; Bioinformatics; FACS of neurons; Expression profiling with
Affymetrix GeneChip arrays; Calcium imaging; Patch Clamp Electrophysiology.
