Our laboratory investigates the role of the Epstein-Barr virus in the etiology of human disease. EBV is a ubiquitous infectious agent, which is associated with specific malignancies including Burkitt's lymphoma, Hodgkin's lymphoma, and nasopharyngeal carcinoma (NPC), which develop with high incidence in endemic areas. EBV is etiologic for post-transplant lymphoma and also causes the AIDS-associated disease, hairy leukoplakia (HLP). We have identified three viral genes, which are consistently expressed and have identified a new family of transcripts that are expressed at particularly high levels in NPC tissue. These new mRNAs are intricately spliced and contain several new open reading frames which could potentially code for protein. We have shown one of these open reading frames does encode a protein that is expressed at high levels in EBV associated cancers. Current studies are investigating the potential functions of this gene using the two hybrid analysis in yeast cells and by determining its intracellular location with confocal microscopy.
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 doesn’t.
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.
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
We examine dynamic cellular processes using structural biology. Current projects focus on Infectious disease, particularly the spread of antibiotic resistance and host-pathogen interactions; Protein-DNA complexes involved in DNA manipulation; the Design of protein therapeutics; Nuclear receptors in transcriptional control; and Enzymes central to drug recognition and metabolism.
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.
My interests include the use of immunological and molecular probes to study function of normal and abnormal coagulation factors; the study of factors regulating human immune response to coagulation factors; and immunochemical studies of antigen-antibody interaction.
The Chromosomal Stability Group integrates mechanisms and genetic controls of genome stability with environmental factors and stress responses to better understand their complex contributions to human health. Using budding yeast and human cell models, research focuses on genome maintenance and natural or environmental challenges to chromosome stability. Repair, replication and checkpoint functions are investigated to understand sources of genome instability and mechanisms of coping with DNA damage, particularly double-strand breaks. Included in these studies are the roles that human genes and networks, particularly p53, play in stress responses.
The primary research focus is the structure, function and biosynthetic processing of membrane proteins which provide permeability pathways through the membranes of cells. Much of the current work is concentrated on the ion channel protein, CFTR (cystic fibrosis transmembrane conductance regulator) which is absent or dysfunctional in patients with cystic fibrosis. To elucidate the molecular mechanisms of CFTR function, we study single channel properties by electrophysiological techniques, enzymatic activity and physical interaction with other cellular molecules. A major objective of studies with the purified molecule is to obtain 3-dimensional structure information so that small molecules capable of recognizing features of its surface shape can be synthesized and used to modulate its folding and activity.
The nucleus accumbens is a limbic-motor integrator, assimilating memory and drive input and coordinating responsive behavioral output. Anatomical and pharmacological evidence indicates that the core and shell subregions of the nucleus accumbens perform overlapping but distinct roles in motivated behavior. My experiments examine nucleus accumbens core and shell function during ethanol drinking behavior in rats, with particular focus on how dopamine input modulates accumbal activity on the millisecond timescale. I use two approaches: electrophysiological firing patterns of neurons in the nucleus accumbens core and shell are evaluated using multi-electrode arrays, and phasic (subsecond) dopamine activity is evaluated using fast-scan cyclic voltammetry. I am also interested in exploring the pharmacological manipulation of neuronal transmission in the nucleus accumbens, focusing on drugs that have clinical therapeutic value in treating alcoholism.
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.
Ion channels and ionotropic receptors. Molecular mechanisms of ligand binding, channel activation, ion selectivity, and allosteric modulation. Techniques used: Molecular modeling, site directed mutagenesis, heterologous expression in Xenopus oocytes and other cells, chemical modification, and voltage clamp electrophysiology.
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.
