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.
Blood vessel formation in cancer and development; use mouse culture (stem cell derived vessels) and in vivo models (embryos and tumors); genetic, cell and molecular biological tools; how do vessels assemble and pattern?, dynamic image analysis.
Our 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.
Our long term goal is to define the molecular mechanisms of two-component regulatory systems, which are utilized for signal transduction by bacteria, archaea, eukaryotic microorganisms, and plants. Our current focus is to understand the features that control the rates of self-catalyzed phosphorylation and dephosphorylation of response regulator proteins. The kinetics of these reactions vary dramatically (>40,000x) between different pathways and reflect the need to synchronize biological responses (e.g. behavior, development, physiology, virulence) to environmental stimuli. Member of the Molecular & Cellular Biophysics Training Program
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.
Our lab is interested in the role of chromatin-modifying factors and epigenetics in mammalian development and disease. We are particularly interested in two major areas both of which make use of mouse models: (1) the role of BRG1 and SWI/SNF nucleosome-remodeling complexes in various aspects of hematopoiesis including regulation of globin gene expression and inflammation; (2) the role of dietary fiber and gut microflora on histone modifications, CpG methylation, and prevention of colorectal cancer.
Experimental Evolution of Viruses. We use both computational and experimental approaches to understand how viruses adapt to their host environment. Our research attempts to determine how genome complexity constrains adaptation, and how virus ecology and genetics interact to determine whether a virus will shift to utilizing new host. In addition, we are trying to develop a framework for predicting which virus genes will contribute to adaptation in particular ecological scenarios such as frequent co-infection of hosts by multiple virus strains. For more information, and for advice on applying to graduate school at UNC, check out my lab website www.unc.edu/~cburch/lab.
Gene targeting and state-of-the-art phenotyping methods are used to elucidate the reproductive and cardiovascular roles of the adrenomedullin system and to characterize the novel GPCR-signaling mechanism of Adms receptor and RAMPs.
Cross-talk between insulin like growth factor -1 and cell adhesion receptors in the regulation of cardiovascular diseases and complications associated with diabetes
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.
Research in the lab is focused on four major areas - (1) Genetic, cellular, and genomic analyses of Drosophila CNS development, (2) Brain development and behavior, (3) Molecular genetics of gene regulatory pathways, and (4) Control of cell migration and fusion events.
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.
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.
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.
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.
The study of opioid analgesics, with particular focus on opioids that are less likely to produce physical dependence and abuse. Research in the laboratory has examined the relationship between the analgesic effects of opioid analgesics and their interaction with specific opioid receptor types. A more recent research interest includes investigations of genetically-altered mice with relevance to drug dependence and the development of models of mouse behavior for examining behavioral phenotypes related to a range of behavioral disorders.
The research in my lab is divided into two main areas - 1) Atomic force microscopy and fluorescence studies of protein-protein and protein-nucleic acid interactions, and 2) Mechanistic studies of transcription elongation. My research spans the biochemical, biophysical, and analytical regimes.
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.
Our work is focused on understanding how major histocompatibility complex (MHC) molecules function in the immune response to pathogens. This simple question involves the most fundamental aspect of immunology - self/non-self discrimination.
We are interested in uncovering the fundamental systems-wide processes and mechanisms that underlie life, with a human-health focus. We apply a combination of both modern and traditional tools to this pursuit, including bioinformatics, proteomics, microarrays, molecular genetics, bench work, and software development. Current research areas we focus on include: 1) locating the molecular mechanisms that underlie antibiotic tolerance in the bacteria Pseudomonas aeruginosa, to address the threat that drug resistant organisms pose to those with COPD and Cystic Fibrosis; 2) annotation of the human genome with proteomic data, to determine which genes are translated and when, and how those correlate with prevalent diseases such as cancer; 3) development of computational agent-based models of intramolecular pathways and pathogen-host interactions in HIV, to determine how host-pathogen interactions relate to disease progression; 4) development of software tools for analysis of RNA structures, such as the viral HIV genome, to assist with determining how RNA structure impacts function; and 5) developing software for finding post-translational modifications (PTMs) on proteins by integrating proteomic data sets, to determine the role that these play on cellular signaling in healthy and diseased states. We have a wide diversity lab members, from microbiology bench scientists to computer scientists, and would be a great fit for a student looking for a broad, cross-disciplinary training environment focused on either microbiology and/or genomics.
Dr. Gilmores research group is applying state-ofthe-art magnetic resonance imaging and image analysis techniques to study human brain development in 0-6 year olds, with a focus on cortical gray and white matter development. Studies include normally developing children, twins, and children at high risk for schizophrenia and bipolar illness. We are beginning to study the contributions of specific genes of risk to brain development in humans. A collaborative study with the Harlow Primate Lab at the University of Wisconsin is using imaging to study brain development in Rhesus monkeys, and the impact of prenatal exposure to maternal infection on brain development.
Successful respiratory pathogens must be able to respond swiftly to a wide array of sophisticated defense mechanisms in the mammalian lung. In histoplasmosis, macrophages -- a first line of defense in the lower respiratory tract -- are effectively parasitized by Histoplasma capsulatum. We are studying this process by focusing on virulence factors produced as this "dimorphic" fungus undergoes a temperature-triggered conversion from a saprophytic mold form to a parasitic yeast form. Yersinia pestis also displays two temperature-regulated lifestyles, depending on whether it is colonizing a flea or mammalian host. Inhalation by humans leads to a rapid and overwhelming disease, and we are trying to understand the development of pneumonic plague by studying genes that are activated during the stages of pulmonary colonization. [note: Dr. Goldman will be moving to UNC in Summer 2008]
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 research goal is to understand how bacterial pathogens cause disease on their hosts. We are working with a plant pathogen, Pseudomonas syringae which introduces virulence proteins into host cells to suppress immune responses. Our laboratory collaborates with Jeff Dangl's lab in the UNC Biology Department using genomics approaches to identify P. syringae virulence proteins and to discover how they alter plant cell biology to evade the plant immune system and cause disease.
The Gupta group uses statistical and computational approaches to find conserved stochastic patterns or motifs in genome sequences. They are particularly interested in using these approaches to discover gene regulatory modules and interaction networks involved in specific biological processes.
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.
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.
Our research is in two areas. First, we are investigating the pathogenesis of Venezuelan equine encephalitis virus (VEE). In the mouse model of VEE infection, we are examining the lymphotropic and neurotropic aspects of the disease, the initial cells targeted after inoculation, the role of viremia in invasion of the central nervous system (CNS), immune mechanisms of clearance from the CNS, and the genetics of pathogenesis. The second research area is the design of live virus vaccines, vaccine vectors and vaccine adjuvants. In animal models of several important human and animal pathogens, e.g. influenza, Marburg, Ebola, dengue fever and simian immunodeficiency virus, VEE vectored vaccines and adjuvants have proven safe, immunogenic and in most cases, protective.
The goal of my research is to identify, clone, and characterize the evolution of genes underlying natural adaptations in order to determine the types of genes involved, how many and what types of genetic changes occurred, and the evolutionary history of these changes. Specific areas of research include: 1) Genetic analyses of adaptations and interspecific differences in Drosophila, 2) Molecular evolution and population genetics of new genes and 3) Evolutionary analysis of QTL and genomic data.
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.
My research aims at prevention and treatment of cardiovascular diseases and focuses on the identification of genes that confer susceptibility or resistance to the diseases with the use of genetically engineered mice. In collaboration with Dr.Oliver Smithies, I very recently developed a new method for altering gene expression by modifying 3 untranslated regions in mice which enables fine-tuned modification of gene expression. I am now analyzing the phenotypes of several mouse models generated with this method.
My lab studies the pathogenic mechanisms of two bacterial pathogens, Haemophilus ducreyi and Francisella tularensis. H. ducreryi, the agent of the sexually transmitted infection chancroid, somehow inhibits the development of an effective immune response
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.
We have used gene targeting to generate an animal model for the most common genetic disease in the Caucasian population, cystic fibrosis. We are continuing to characterize this animal and to modify it to produce a disease that more closely resembles human cystic fibrosis. A second area in which our lab is interested involves the study of the inflammatory processes involved in allergic responses, asthma, and arthritis. Our current efforts are aimed at generating animals deficient in various factors that are believed to be important in these diseases. By providing us with a better understanding of the immunological processes that underlie allergic responses, asthma and arthritis, these animals should help us to identify more effective treatments for these diseases.
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.
Dr. Langes primary research interests are in the development and application of statistical methods to genetic data. His methodological work has focused on developing techniques for haplotype-based association analyses, linkage analysis, and genetic power analyses.
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.
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.
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.
My laboratory studies diffuse gliomas, devastating primary tumors of the central nervous system for which few effective drugs are currently available. We utilize model systems (genetically engineered mice, cultured cells, and human tumor specimens) to explore the molecular pathogenesis of
and develop drugs and diagnostic markers for individualized therapy of gliomas. Rotating students gain experience with techniques that include genomics (expression microarrays and array CGH), fluorescence microscopy, computer-enhanced image analysis, and tissue microarrays.
Molecular genetic analysis of virulence of Yersinia and Klebsiella: My laboratory uses Yersinia enterocolitica, Y. pestis, and Klebsiella as model systems to study bacterial pathogenesis. The long-term goals of our work are to understand the bacteria-host interaction at the molecular level to learn how this interaction affects the pathogenesis of infections and to understand how these pathogens co-ordinate the expression of virulence determinants during an infection. To do this we use genetic, molecular and immunological approaches in conjunction with the mouse model of infection. [Note: I will be moving my laboratory to UNC-CH in the summer of 2008]
Dr. Millikan's research interests include the role of genetics in human cancer, including the study of how inherited variation in DNA repair interacts with environmental factors in breast cancer, colon cancer, and malignant melanoma. He is also interested in carcinogen metabolism, and identifying causes of breast cancer in young women and African American women.
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 focuses on understanding the relationship between dermal and inhalation exposure and the effect of individual genetic differences on the function of enzymes that detoxify hazardous agents and that affect the development of disease. My research group has pioneered approaches to quantitatively measure skin and inhalation exposures to toxicants; additionally, my group has developed sophisticated exposure modeling tools using mathematical and statistical principles in an effort to standardize and improve exposure and risk assessment.
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.
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.
Human carcinomas show great diversity in their morphologies, clinical histories and in their responsiveness to therapy. This wide tumor diversity poses the main challenge to the effective treatment of cancer patients. The main focus of the Perou Lab is to characterize the biology diversity of human tumors using microarray analysis, genomics, molecular genetics, and cell biology, and then to mimic these findings in animal models. We ultimately use these animal systems to develop predictive computational models and to test new therapeutics that are specific for each tumor subtype.
The main focus of our research is to examine the molecular and cellular mechanisms that are involved in conferring neural identity to stem cells during embryogenesis and the adult.
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. Pomp studies the genetic architecture of complex traits, with an emphasis on body weight regulation and obesity. Using polygenic mouse models and high throughput approaches integrating genomics and physiology, he identifies genes that control predisposition to a variety of complex traits including energy intake and energy expenditure (e.g. voluntary exercise). In addition, Dr. Pomp studies how these genes interact with each other, with changing environments such as nutritional interventions, and with other diseases such as cancer.
The long term goal of our research is to understand mechanisms underlying homologous chromosome pairing and
genetic recombination during meiosis. We have developed the
basidiomycete fungus Coprinus cinereus as a model system for analysis of meiosis. We are currently utilizing transcriptional profiling of the recently annotated genome to analyze the genetic controls of chromosome pairing. We have also constructed a high-resolution genetic map of the
13 sequenced chromosomes to examine chromosomal sites that act autonomously to initiate synapsis.
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.
The intestine harbors a large and diverse community of microorganisms. This gut microbiota impacts upon many aspects of host biology, including nutrient metabolism, immunity, and epithelial cell renewal. Our lab is using genetic and molecular methods in gnotobiotic zebrafish hosts and in selected members of the gut microbiota, to investigate the mechanisms underlying evolutionarily-conserved host-microbial interactions in the vertebrate digestive tract.
Keywords: intestine, microbiota, bacteria, symbiosis, commensalism, immunity, inflammation, metabolism, obesity, germ-free, gnotobiotics, zebrafish
Regulation of plant development: We use techniques of genetics, molecular biology, microscopy, physiology, and biochemistry to study how endogenous developmental programs and exogenous signals cooperate to determine plant form. The model plant Arabidopsis thaliana has numerous technical advantages that allow rapid experimental progress. We focus on how the plant hormone auxin acts in several different developmental contexts. Among questions of current interest are i) how auxin regulates patterning in embryos and ovules, ii) how light modifies auxin response, iii) how feedback loops affect kinetics or patterning of auxin response, iv) how flower opening and pollination are regulated, and v) whether natural variation in flower development affects rates of self-pollination vs. outcrossing.
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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.
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.
Our long term goals are to better define mechanisms of chronic intestinal inflammation and to identify areas for therapeutic intervention. Research in our laboratories is in the following four general areas: 1) Induction and perpetuation of chronic intestinal and extraintestinal inflammation by resident intestinal bacteria and their cell wall polymers, 2) Mechanisms of genetically determined host susceptibility to bacterial product,. 3) Regulation of immunosuppressive molecules in intestinal epithelial cells and 4) Performing clinical trials of novel therapeutic agents in inflammatory bowel disease patients.
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.
Correction of genes with mutant pathologies (gene therapy); construction of animal models of human genetic diseases to facilitate better studies of the resultant pathology and develop new modes of treatment.
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.
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.
I study complex traits using linkage, association, and genetic epidemiological approaches. Disorders include schizophrenia (etiology and pharmacogenetics), smoking behavior, and chronic fatigue.
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.
The goal of our research is to identify signaling mechanisms that contribute to normal and pathophysiological cell growth in the cardiovascular system. We study cardiac and vascular development as well as heart failure and atherosclerosis.
Our laboratory uses the mouse as a model to study phenotypes with complex etiologies contributed by genetic and environmental factors and that underlie differences in susceptibility to common diseases. Genetics and a broad range of genomic, bioinformatic and computational tools are used in a new integrative field called systems genetics. Through many collaborative interactions, major research foci are currently in development, reproduction, neurobiology, cancer (colon and breast), cardiology, exposure biology and computational genetics. Our laboratory is also investigating the function role of the Egfr/Erbb gene family of receptor tyrosine kinases through embryonic stem cell manipulation, transgenics, gene targeting and other genetic engineering technologies.
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.
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.
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.
My lab concentrates on studying the molecular genetic basis of the evolutionary processes of adaptation and speciation. The questions we ask are what are the sequence changes that lead to variation between species and diversity within species, and what can these changes tell us about the processes that lead to their evolution. We use a number of different techniques to answer these questions, including molecular biology, sequence analyses (i.e. population genetics and molecular evolution techniques), physiological studies, and examinations of whole-organism fitness. Currently work in the lab has focused on a intertidal copepod species that is an excellent model for the initial stages of speciation (and also provides opportunities to study how populations of this species adapt to their physical environment).
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.
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.
