Eukaryotic Gene Regulation and Cancer Molecular Biology
We are interested in the mechanisms that regulate gene expression in eukaryotes, and the role of gene expression in various human disease states. To pursue these interests we use transcription-based approaches and functional screens to identify new genes and regulatory pathways involved in cancer. These studies are intended to enhance our understanding of how normal cells become cancerous and reveal potential new targets for therapeutic intervention.
Molecular Genetics of Lipid Metabolism and Signaling
One of the major goals of our laboratory is to understand how organisms integrate sphingolipid biosynthesis and trafficking with their dual function as structural components of membranes and as second messengers. It is our hope that understanding networks that control normal sphingolipid homeostasis and function will provide opportunities for therapeutic strategies to treat diseases associated with alterations in sphingolipid metabolism.
Neuronal Cell Fate Specification
A fundamental question in biology is how protein complexes consisting of multiple proteins regulate basic biological processes such as embryogenesis and, when disturbed, cause cancer. Our laboratory investigates the molecular mechanisms that underlie neuronal cell fate specification events during embryogenesis using the protein network around LIM domains as a model system.
Regulation of Cell Growth and Division
Misregulation of cell division is the underlying cause of a number of human diseases, including cancer. Our lab is interested in understanding the molecular mechanisms that control how cells grow and divide. We study how protein degradation by the ubiquitin proteasome system controls both the cell cycle and metabolic transitions.
Drosophila p53 and DNA Damage-Induced Apoptosis
The overall goal of our lab is to understand how animal cells coordinate cell proliferation and cell death during development. To approach this problem, we are studying the regulation of apoptosis and cell cycle arrest following DNA damage in the fruit fly Drosophila melanogaster.
Genetics of Leukemia, Mouse Models
Research in our lab focuses on understanding the molecular mechanisms directing leukemia development. In particular, we seek to understand the transcriptional and signaling alterations defined by activation of the acute myeloid leukemia fusion oncogenes CBFβ-MYH11 and CBFβ-SMMHC in hematopoietic stem cells and other early progenitors, and to characterize the genetic alterations that synergize with these fusion oncogenes during leukemia progression.
Spatial Organization of Genomes
Many diseases, including cancer, are characterized by alterations in the spatial organization of the genome. How genomes are organized in three dimensions, and how this affects gene expression is poorly understood. To address this issue we are studying how the human and yeast genomes are organized into three dimensions inside the nucleus using a set of powerful molecular and genomic tools that we have developed.
Chromatin Regulation in Stem Cells
In eukaryotes, relatively large amounts of DNA must be packed into microscopic nuclei within each cell, which is achieved via the formation of highly organized, yet dynamic chromatin structure. We are interested in the mechanisms by which chromatin structure and chromatin regulatory proteins impact gene expression, self-renewal and differentiation in stem cells. To study these processes, we utilize an array of molecular, cellular, genetic, biochemical and systems level approaches.
Molecular Biology of HIV-1
The overall goal of the lab is to understand at the molecular level how an infectious HIV-1 virus particle is formed and what cellular proteins are involved. Additionally, we use HIV as a model system to elucidate how the human class E Vps machinery functions in protein sorting and vesicular transport. We expect that these studies will provide insights into the mechanism of virus release, virus spreading via cell-to-cell transmission, and the unique ability of lentiviruses such as HIV-1 to infect non-dividing, terminally differentiated cells.
Assembly and Function of Eukaryotic Chromosomes
We study several different classes of proteins used by eukaryotic cells to deposit histones onto DNA, as well as enzyme complexes that chemically modify histones in order to alter their function. We study these processes in yeast and human cells, using biochemical, genetic, genomic, and cell biological techniques.
Determining the Signals Responsible for Blood Vessel Development using Zebrafish
Research in our lab focuses on vascular development. Using zebrafish as a model system, we study the factors involved in shaping endothelial cell differentiation and blood vessel identity, how cell behaviors are coordinated during angiogenesis, and the role of hemodynamics in shaping blood vessels. Recently we have applied the use of zinc-finger nucleases to make zebrafish knockouts.
Molecular Genetics of Pancreatic and Liver Cancers
Human solid tumors are marked by the presence of multiple genetic and epigenetic alterations. Although many of the genetic alterations that occur within particular tumor types have been identified, the specific molecular events that occur downstream of these genetic changes, and the mechanisms by which they influence tumor initiation, progression, and metastasis are still poorly understood. We have used the RCAS-TVA gene delivery system to generate mouse models for pancreatic and hepatic carcinomas, and we use these mice to identify correlations between specific genetic changes, tumor behavior, and signal transduction pathways.
Dissecting Molecular Mechanisms of the Aging Process
What determines how we age? What defines how long we will live? Is this a clock that is set from birth? How can we tinker with this clock? These are the questions we seek to address in the lab. The ultimate goal of our work is to increase the healthy. reproductive years of individuals; redefining and prolonging healthy middle age. Research in our lab uses the nematode C. elegans as a model system to study the aging process.
Molecular Pathogenesis of Facioscapulohumeral Muscular Dystrophy
Research in my lab focuses on studying the molecular pathogenesis of facioscapulohumeral muscular dystrophy (FSHD), the third most common inherited myopathy. FSHD is not the result of a classical mutation within a protein-coding gene, but is instead due to transcriptional misregulation of genes located in the subtelomeric region of chromosome 4q35. Research in our lab is focused on delineating the molecular mechanism(s) that lead to abnormal transcriptional regulation at 4q35, with the ultimate goal of advancing the understanding of the pathogenesis of FSHD.
Mapping Transcription Regulatory Circuits in the Nematode C. elegans
We use a variety of experimental and computational systems biology approaches to map and characterize gene regulatory networks and to understand how regulatory circuitry controls animal development, function, and homeostasis. Ultimately, we aim to understand how dysfunctional networks affect or cause diseases like diabetes, obesity and cancer.
Transcriptional Control of Energy Metabolism and Metabolic Diseases by the Nuclear Receptor PPAR Subfamily
Normal cellular energy metabolism is maintained through a delicate balance between energy intake and energy expenditure. When energy intake exceeds energy expenditure, the extra energy is stored in the form of fat. This energy imbalance is intimately linked to a cluster of metabolic diseases, including obesity, hyperlipidemia, and cardiovascular disease, as well as insulin resistance and type 2 diabetes. Our laboratory is interested in understanding the transcriptional control of fatty acid and glucose metabolism by the PPAR subfamily of nuclear receptors.
Creating Artifical DNA-Binding Domains for Targeted Gene Regulation and Gene Modification
My research program is focused on three inter-related areas: (1) understanding fundamental aspects of protein-DNA recognition; (2) engineering artificial transcription factors for targeted gene regulation and modification; and (3) developing selection technologies to characterize and engineer protein-DNA interactions. The goals of these studies are to provide a valuable resource for understanding specificity determinants for rationally engineering the specificity of DNA-binding domains, and, ultimately, to revolutionize reverse genetic approaches in model organisms, which may allow the straightforward creation of tailor-made human disease models with profound implications for the development of treatments for a variety of diseases.
Computational Biology and Bioinformatics
The purpose of our group is to provide bioinformatics support to the research community in PGFE. Our areas of greatest interest include data integration and data mining of high-throughput experiments such as ChIP-seq, ChIP-chip and microarrays. Working with PGFE researchers, we aim to develop and apply computational tools to analyze and integrate various data sources.