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.
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.
The goal of our laboratory is to investigate mechanisms of tumorigenesis and tumor progression, and to apply genome-wide techniques to develop anti-cancer therapies. Our research focuses on transcriptional regulation of gene expression during stem cell self-renewal and differentiation and during tumorigenesis. We use artificial transcription factors (ATFs) as genetic probes to identify genes and gene pathways responsible for the appearance of specific malignant phenotypes and we investigate the ability of these ATFs to interfere with tumor cell regulatory programs. Cancer cell reprogramming with such artificial �genetic switches� may afford a new therapeutic strategy.
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.
The Cancer Biology Group at NIEHS focuses on early events in skin tumor development using a transgenic mouse model (TgAC). This model possesses a v-Ha-ras transgene under the regulation of a fetal globin promotor integrated at an ectopic site which confers a unique phenotype of inducible skin papillomas with a high rate of progression to invasive squamous and spindle cell neoplasms. The goals of our studies are to identify and characterize: 1) The cellular origin of the tumors and 2) critical genes which are involved in ras-mediated tumor induction and progression. Conventional cancer therapies have until recently depended on treatment late stages of tumor growth and involved non-specific mechanisms of cellular injury. By focusing on understanding early events in tumor induction we hope to gain insights into targets for intervention that can more specifically inhibit cancer cell growth.
Steroid hormones regulate tissue-specific gene expression in animals via receptor dependent intracellular signal transduction pathways. We are particularly interested in glucocorticoid receptors and their actions on the immune system because they reflect the primary response to environmental stress. Current research projects are examining the following aspects of glucocorticoid hormone action. A second major interest of the laboratory focuses on evaluating the mechanisms involved in the regulation of apoptosis in normal and neoplastic cells. Research is aimed at the identification and cloning of genes that are responsible for both the initiation and execution of apoptosis.
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.
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.
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.
1) Identification of critical elements of human genetic variability contributing to pain sensitivity and pathophysiological pain states, 2) identification of therapeutic targets for pain management, 3) studying molecular hierarchy of functional SNPs commonly present in human population and 4) studying the molecular mechanisms of gene expression regulation.
We use an integrated approach (genomics, proteomics, computational biology) to study the molecular mechanisms of hormone and drug desensitization. Our current focus is on RGS proteins (regulators of G protein signaling) and post-translational modifications including ubiquitination and phosphorylation.
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.
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.
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.
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.
Dr. Lange�s 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.
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.
Molecular, cellular and in vivo approaches in intestine to define mechanisms by which hormones and growth factors regulate normal growth and cancer. Uses model cell lines, mutant mice, mouse models of disease, translational approaches to growth factor action and signal transduction, gut immune interactions in obesity.
The Magnuson Lab works in three areas - (i) Novel approaches to allelic series of genomic modifications in mammals, (ii)Mammalian polycomb-group complexes and development, (iii) Mammalian Swi/Snf chromatin remodeling complexes
We 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.
My laboratory studies diffuse gliomas, devastating primary tumors of the central nervous system for which few effective drugs are currently available. We utilize model systems (genetically engineered mice, cultured cells, and human tumor specimens) to explore the molecular pathogenesis of
and develop drugs and diagnostic markers for individualized therapy of gliomas. Rotating students gain experience with techniques that include genomics (expression microarrays and array CGH), fluorescence microscopy, computer-enhanced image analysis, and tissue microarrays.
We are identifying genetic variants that influence common human traits with complex inheritance patterns, and we seek to understand the biological function of the identified variants. Currently we are investigating susceptibility to type 2 diabetes and obesity, as well as variation in cholesterol levels, blood pressure, body size, weight gain and early growth. In addition to examining the primary effects of genes, the lab is exploring the interaction of genes with environmental risk factors in disease pathogenesis. Approaches include genome-wide association studies, genetic epidemiology, resequencing, bioinformatic analysis, molecular biology, cell biology, and mouse models to compare high- and low-risk alleles in a whole-animal setting.
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.
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.
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.
High-performance computing: algorithms, programming languages, compilers and architectures. Scientific computing with focus on computational biology and bioinformatics. High-level programming languages and problem solving environments.
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.
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 Chromosomal Stability Group integrates mechanisms and genetic controls of genome stability with environmental factors and stress responses to better understand their complex contributions to human health. Using budding yeast and human cell models, research focuses on genome maintenance and natural or environmental challenges to chromosome stability. Repair, replication and checkpoint functions are investigated to understand sources of genome instability and mechanisms of coping with DNA damage, particularly double-strand breaks. Included in these studies are the roles that human genes and networks, particularly p53, play in stress responses.
The research in our lab is centered on understanding the mechanisms and principles of movement at the cellular level. Cytoskeletal filaments - composed of actin and microtubules - serve as a structural scaffolding that gives cells the ability to divide, crawl, and change their shape. Our lab uses a combination of cell biological, biochemical, functional genomic, and high resolution imaging techniques to study cytoskeletal dynamics and how they contribute to cellular motion.
Bioinformatics, Cancer Biology, Cell Biology, Chemical Biology, Computational Biology, Genomics, Molecular Medicine, Neurobiology, Pharmacology, Systems Biology, Toxicology, Translational Medicine
Our laboratory applies molecular, biochemical, genetic and genomics approaches to understanding the mechanisms of environmental agent-related organ injury and carcinogenesis. Specifically, we are interested in nuclear receptor-mediated pathways in chemical carcinogenesis, oxidative DNA damage and repair, the role that alcohol and diet play in cancer, and the genetic determinants of the susceptibility to toxicant-induced liver injury. Through a combination of in vivo animal studies and experiments that utilize cellular and molecular models, we aim to better understand why certain chemicals cause cancer or organ damage in rodents and whether humans in general, or any susceptible sub-population in particular, are at risk from similar exposures.
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.
I study complex traits using linkage, association, and genetic epidemiological approaches. Disorders include schizophrenia (etiology and pharmacogenetics), smoking behavior, and chronic fatigue.
The Cancer Biology Group at NIEHS focuses on early events in skin tumor development using a transgenic mouse model (TgAC). This model possesses a v-Ha-ras transgene under the regulation of a fetal globin promotor integrated at an ectopic site which confers a unique phenotype of inducible skin papillomas with a high rate of progression to invasive squamous and spindle cell neoplasms. The goals of our studies are to identify and characterize: 1) The cellular origin of the tumors and 2) critical genes which are involved in ras-mediated tumor induction and progression. Conventional cancer therapies have until recently depended on treatment late stages of tumor growth and involved non-specific mechanisms of cellular injury. By focusing on understanding early events in tumor induction we hope to gain insights into targets for intervention that can more specifically inhibit cancer cell growth.
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.
"Our lab uses computational and molecular tools to study the evolution of genome organization, primarily in the flowering plants. Areas of
investigation include the origin and consequences of differences in gene order within populations and between species, the evolutionary and functional diversification of gene families (phytome.org), and the application of genomics to evolutionary model organisms (mimulusevolution.org). We also are involved in a number of cyberinfrastructure initiatives through the National Evolutionary Synthesis Center (nescent.org), including work on digital scientific libraries(datadryad.org), open bioinformatic software development (e.g. gmod.org) and the application of semantic web technologies to biological data integration(phenoscape.org)."
The Wang group designs novel data models and algorithms to address fundamental computational issues in analyzing large sets of experimental data. Ongoing research projects include: 1) Classification and clustering analysis of gene-expression profiles, 2) Discovery of discriminative structural motifs in proteins and 3) Query and integration of heterogeneous databases.
The Wilhelmsen lab is engaged in the genetic mapping of susceptibility loci for complex neurological diseases and has been developing large-scale automated gene mapping technologies to facilitate these mapping efforts. They have invested heavily in automation that enables high-throughput genotyping and data processing. As data accumulates, this will enable parametric and nonparametric linkage analysis of large numbers of traits at regular intervals for the entire genome. The Wilhelmsen lab is applying these techniques to two projects: (1) the genetics of alcoholism and (2) positional cloning of the gene responsible for a family of disorders called frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).
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.
