Our research group utilizes the nematode C. elegans to investigate germ cell immortality: mechanisms that allow germ cells remain eternally youthful as they are transmitted from one generation to the next. We also study how telomerase functions at chromosome termini, as well as the consequences of telomere dysfunction.
Research is aimed at evaluating genetic and epigenetic mechanisms in environmental chemical carcinogenesis. Specific project areas are concerned with toxicity assessments of conazole pesticides, arsenic, and water
disinfection by-products. Human and rodent cells are analyzed for chemical-induced alterations in DNA
methylation and gene expression in combination with chromosome damage, cell toxicity and histopathological
effects. Ultimate goals are to improve the scientific basis of risk assessment, and include evaluations of lifestage
and nutritional susceptibility risk factors which may modulate chemical toxic/carcinogenic effects.
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).
Coronaviruses, including SARS and Noroviruses are used as models to study the genetics of RNA virus transcription, replication, persistence, cross species transmission and vaccine development.
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.
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.
Molecular evolution and mechanistic enzymology find powerful synergy in our study of aminoacyl-tRNA synthetases, which translate the genetic code. Class I Tryptophanyl-tRNA Synthetase stores free energy as conformational strain imposed by long-range, interactions on the minimal catalytic domain (MCD) when it binds ATP. We study how this allostery works using X-ray crystallography, bioinformatics, molecular dynamics, enzyme kinetics, and thermodynamics. As coding sequences for class I and II MCDs have significant complementarity, we also pursuing their sense/antisense ancestry. Member of the Molecular & Cellular Biophysics Training Program.
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 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.
The primary research area my lab is the regulation of meiotic recombination at the genomic level in higher eukaryotes. Genomic instability and disease states, including cancer, can occur if the cell fails to properly regulate recombination. We have created novel tools that give our lab an unparalleled ability to find mutants in genes that control recombination. We use a combination of genetics, bioinformatics, computational biology, cell biology and genomics in our investigations. A second research area in the lab is the role of centromere DNA in chromosome biology. We welcome undergraduates, graduate students, postdoctoral fellows and visiting scientists to join our team.
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.
With a particular interest in pediatric solid tumors, our lab aims to develop a mechanistic understanding of the role of aberrant or dysregulated transcription factors in oncogenesis.
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 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.
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.
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.
The role of associative learning and memory in cue-induced relapse to drug seeking and the role of the prefrontal cortex in suppression of drug seeking. Studies in my laboratory utilize surgical, behavioral, and histological techniques as well as neuropharmacological manipulations.
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.
We are interested in basic DNA-protein interactions as related to - DNA replication, DNA repair and telomere function. We utilize a combination of state of the art molecular and biochemical methods together with high resolution electron microscopes.
My 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.
We study alphavirus infection to model virus-induced disease. Projects include 1) mapping viral determinants involved in encephalitis, and 2) using a mouse model of virus-induced arthritis to identify viral and host factors associated with disease.
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.
Our lab is focused on the development of HIV-1 vectors for gene therapy of genetic disease. In addition, we are using the vector system to study HIV-1 biology. We are also interested in utilizing the HIV-1 vector system for functional genomics.
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.
Hormones influence virtually every aspect of plant growth and development. My lab is examining the molecular mechanisms
controlling the biosynthesis and signal transduction of the
phytohormones cytokinin and ethylene, and the roles that these hormones play in various aspects of development. We employ genetic, molecular, biochemical, and genomic approaches using the model species Arabidopsis to elucidate these pathways.
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.
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.
We use high-throughput DNA sequencing, microarrays, and other technologies to study how and where proteins interact with the genome, and how these interactions affect the biology of living cells. We use three systems: yeast, C. elegans and human. Our C. elegans studies focus on developmental processes, and we use human cell lines and clinical samples to study diseases like cancer and diabetes. All of our projects focus on chromatin and DNA-binding proteins.
Specialized cell types allow plants to shed their structures-such as leaves, flowers and fruit-through the carefully orchestrated process of cell separation. The research focus of the Liljegren lab is to investigate the molecular mechanisms that control cell separation using the Arabidopsis flower as a model system. As in many other higher plants, Arabidopsis flowers contain pattern elements which allow distinct separation events such as floral organ shedding, fruit opening, pollen dehiscence, and seed dispersal to take place during their life cycle. Currently, we are characterizing the functions of key regulators of floral organ separation, including NEVERSHED, LOVES-ME-NOT and STAMENSTAY. We have discovered that NEVERSHED regulates vesicle trafficking during flower development and are using sensitized genetic screens to identify additional components of a signaling pathway, such as the receptor-like kinase EVERSHED, that likely control the movement and secretion of specific molecules during the shedding process.
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
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.
The overall goal of our laboratory is to obtain new insights into the host-virus interaction, particularly in HIV infection, and translate discoveries in molecular biology and virology to the clinic to aid in the treatment of HIV infection. A subpopulation of HIV-infected lymphocytes is able to avoid viral or immune cytolysis and return to the resting state. Current work focuses on the molecular mechanisms that control the latent reservoir of HIV infection within resting T cells. We have found that cellular transcription factors widely distributed in lymphocytes can remodel chromatin and maintain quiescence of the HIV genome in resting CD4+ lymphocytes. These studies give insight into the basic molecular mechanisms of eukaryotic gene expression, as well as new therapeutic approaches for HIV infection.
We are interested in the mechanisms by which histone protein synthesis is coupled to DNA replication, both in mammalian cell cycle and during early embryogenesis in Drosophila, Xenopus and sea urchins.
Research in our laboratory 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.
Research in our laboratory is focused on the enzymatic mechanisms and biological roles of DNA helicases. These enzymes provide the primary mechanism by which duplex DNA is converted to single-stranded DNA (ssDNA) for use as a template in DNA replication and repair or as a substrate in recombination. Indeed, these enzymes are essential for DNA replication, repair and to maintain genomic stability in all organisms. Consistent with this idea, defects in genes encoding DNA helicases in human cells have been linked to genomic instability leading to a variety of progeriod disorders and human cancers. The bacterium E. coli and the budding yeast S. cerevisiae provide attractive systems in which to pursue these studies due to the ease of genetic manipulation and the ability to isolate enzymes for biochemical studies. The long-range goal of the research program is to understand, in enzymatic and molecular terms, the mechanism of action of several helicase enzymes, and to define their individual roles in DNA metabolism.
The lab also has an interest in the process of DNA transfer by bacterial conjugation, first observed more than 50 years ago as the unidirectional and horizontal transmission of genetic information from one E. coli cell to another. Today we know that conjugative DNA transfer plays a role in increasing genetic diversity in addition to propagating the spread of antibiotic resistance and microbial virulence factors. Recent work in this laboratory and others has provided a working model of DNA transfer in the F plasmid system. The long-range goal of this research program is to define the function and regulation of the relaxosome, and each protein in this nucleoprotein complex, in conjugative DNA transfer. Based on that information we will begin to establish inhibitors of relaxosome function.
There are two ongoing projects in my lab - mechanism of binding of bacteria to plant surfaces and mechanism of carbohydrate synthesis in bacteria. We are studying the mechanisms of adhesion of the plant pathogenic and symbiotic bacteria Agrobacterium and Rhizobium to plant hosts. This binding involves protein adhesins, pilus adhesins, and carbohydrates. We are also studying the mechanisms of adhesion of the human pathogens E. coli O157 and Salmonella enterica to plant surfaces. The presence of human pathogens on produce and ready to eat fresh food has emerged as a serious concern worldwide. These bacteria bind tightly to the plant surface and can not be removed by washing. Understanding how these bacteria bind to plants is critical to preventing or inhibiting their binding and thus reducing their transmission via this route.
The second project in my laboratory concerns the mechanism of biosynthesis of polysaccharides by bacteria. We are particularly interested in cellulose and curdlan which are synthesized from the same precursor using similar proteins. We would like to understand the differences between these proteins which cause one to catalyze the synthesis of cellulose and the other to catalyze the synthesis of curdlan. We are also interested in the regulation of the biosynthesis of these exopolysaccharides, particularly in the role of cyclic diguanylic acid in this regulation.
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.
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.
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
The end joining pathway is a major means for repairing chromosome breaks in vertebrates. My lab is using cellular and cell-free models to learn how end joining works, and what happens when it doesnt.
Identification of airway epithelial stem cells; innate immunity in the airway; the pathophysiology of post-lung transplant ischemia reperfusion injury and bronchiolitis obliterans syndrome.
The focus of my research group is the tumorigenesis of renal cell carcinoma. Our approach utilizes genetically engineered cells expressing clinically important point mutations in genes identified from renal cancers. Using cellular and animal models we are able to investigate processes integral to tumorigenesis including angiogenesis, hypoxic response signaling, extracellular matrix remodeling, and cell cycle signaling. Using data from the experimental models, I oversee a clinical research program that offers biologically active protocols to patients with renal cell carcinoma and examines correlative radiographic and serum or tumor biomarkers of tumor response to treatment.
We are engaged in studying the molecular biology of the human parvovirus adeno-associated virus (AAV) with the intent to using this virus for developing a novel, safe, and efficient delivery system for human gene therapy.
We have three main areas of research focus: (1) Nucleotide excision repair: The only known mechanism for the removal of bulky DNA adducts in humans. (2) DNA damage checkpoints: Biochemical pathways that transiently block cell cycle progression while DNA contains damage. (3) Circadian rhythm: The oscillations in biochemical, physiological and behavioral processes that occur with the periodicity of about 24 hours.
My lab is interested in mechanisms that (1) fine tune gene expression and (2) coordinate transcription and RNA processing in eukaryotes. Our work is based on molecular, genetic and biochemical analysis of the suppressor of sable gene of Drosophila.
Genome instability is a major cause of cancer. We use the model organism Drosophila melanogaster to study maintenance of genome stability, including DNA double-strand break repair,
meiotic and mitotic recombination, and characterization of fragile sites in the genome. Our primary approaches are genetic (forward and reverse, transmission and molecular), but we are also using biochemistry to study protein complexes of interest, genomics to identify fragile sites and understand the regulation of meiotic recombination, fluorescence and electron microscopy for analysis of mutant phenotypes, and cell culture for experiments using RNA interference.
The 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.
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.
We are combining biochemistry and molecular biology to study protein synthesis in mammalian mitochondria. Factors required for the initiation and elongation steps of have been cloned and detailed protein chemistry is being carried out to study their properties. Mutations of several of these proteins are lethal in humans and these mutations are being studied to study the interactions of these factors with ribosomes and the structures of these factors bound to ribosomes are being examined using cryoelectron microscopy. Chemical probing is being used to explore the structures of mitochondrial mRNAs. The tRNAs in mammalian mitochondria are quite unusual and mutations in them can cause human diseases. The underlying defects in these tRNAs are being probed at structural and biochemical levels providing an understanding of how the mutations lead to human disease.
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.
Our laboratory is examining the role of histone post-translational modifications in chromatin structure and function. Using a combination of molecular biology, genetics and biochemistry, we are determining how a number of modifications to the histone tails (e.g. acetylation, phosphorylation, methylation and ubiquitylation) contribute to the control of gene transcription, DNA repair and replication.
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.
FFirst, we study the complex HIV-1 population that exists within a person. We use this complexity to ask questions about viral evolution, transmission, compartmentalization, and pathogenesis. Second, we are exploring the impact of drug resistance on viral fitness and identifying new drug targets in the viral protein processing pathway. Third, we participate in a collaborative effort to develop an HIV-1 vaccine. Fourth, we are using mutagenesis to determine the role of RNA secondary structure in viral replication.
My laboratory focuses on understanding mechanisms of carcinogenesis, with emphasis on the role of DNA damage and repair. During the last few years, we have developed ultra-sensitive and highly specific mass spectrometry methods for measuring the DNA and hemoglobin adducts of vinyl chloride, crotonaldehyde, ethylene oxide, propylene oxide, styrene oxide, butadiene, malondialdehyde, cis-platin and O6-methyldeoxy-guanosine, as well as slotblot methods for AP sites and oxidative DNA damage. These methods have been applied to understanding critical mechanisms in carcinogenesis, as well as undertaking molecular epidemiology studies of workers in the butadiene and reinforced plastics industries. We are also examining changes in gene expression associated with oxidative stress and environmental chemical exposure.
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.
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.
We are interested in understanding how autoreactive B cells become re-activated to secrete autoantibodies that lead to autoimmune disease. Our research is focused on understanding how signal transduction through the B cell antigen receptor (BCR) and Toll Like Receptors (TLR) lead to secretion of autoantibodies in Systemic Lupus Erythematosus (SLE).
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.
To understand the general rules of splicing regulation, a.k.a. "splicing code", we study the splicing regulation in a systematic way. We also try to engineer molecules that can modulate splicing, and use them as drugs to treat splicing diseases.
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.
How the loss of different components of the SWI/SNF complex contributes to neoplastic transformation remains an open and important question. My laboratory concentrates on addressing this question by the combined use of biological, biochemical and mouse models for SWI/SNF complex function.
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.
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.
Our research focuses on the mechanisms used by the bacterium Pseudomonas aeruginosa to cause disease. We are interested in identifying signal transduction pathways that regulate the expression of virulence genes in response to the host environment.
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.
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.
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.
