Faculty and Research Interests
Our lab studies muscle cells as a model for understanding how embryonic cells adopt specific fates and how programs of cell differentiation and morphogenesis are controlled during development. There are three major muscle cell types: cardiac, skeletal and smooth, which express distinct sets of genes controlled by different combinations of transcription factors and extracellular signals. We have focused on discovering novel transcription factors that control development of these muscle cell types and remodeling in response to cardiovascular and neuromuscular diseases.
The processes involved in muscle development are evolutionarily ancient and conserved across diverse organisms. This conservation has enabled us to take a cross-species approach to dissect this problem by identifying myogenic regulatory genes in the fruit fly or in vertebrate embryos and to use these genes to perform gain and loss-of-function experiments in vivo and in vitro. Most recently, we have explored the roles of microRNAs in the control of muscle development and disease. Our longterm goal is to delineate the complete genetic pathways for the formation and function of each muscle cell type and to use this information to devise pharmacologic and genetic therapies for inherited and acquired muscle diseases in humans. Lab website
The major goal of our lab is to understand the earliest steps in cancer at a molecular level. Our focus is on defining novel cancer genes and on understanding the developmental biology of tumors. To accomplish this, we have turned to the zebrafish system. The zebrafish is a wonderful complement to mouse, fly, worm, and other disease models. The fish produce large numbers of progeny weekly and are easily maintained, allowing us to take large-scale, genome-wide approaches. The transparent embryos develop external to the mother and are accessible to manipulation with transgenic or antisense approaches. At the same time, fish have true vertebrate anatomy and physiology, and are susceptible to the same tumors as are humans, making them an excellent cancer model.
We seek to understand the mechanisms that regulate the balance between stem cell self-renewal and differentiation. We use the germline stem cells of the Drosophila ovary as a model to study stem cell biology because we can identify and genetically manipulate individual cells within their native environment. The molecules we work on tend to fall into two broad categories: Those that regulate chromatin organization and those that modulate mRNA translation. Lab website
Despite advances in our understanding of the ultrastructure of eukaryotic cells, the question of how these cells interact to form the tissues of our bodies is still poorly understood. Once formed, we know even less about how these tissues are maintained. My lab is interested in how groups of cells organize themselves into properly sized, polarized tubules and then how these structures are maintained throughout the life of the organism. This is particularly significant as defects in tubule size and maintenance play causal roles in several human diseases including cystic kidney diseases and cancers. Lab website
We are taking biochemical and genetic approaches to dissect two signaling pathways: ubiquitin-mediated activation of protein kinases and antiviral innate immunity. We have uncovered a novel function of ubiquitin in activating protein kinases in the nuclear factor κB (NF-κB) signaling cascade through a proteasome-independent mechanism. Our current effort is focused on elucidating the biochemical mechanism underlying the regulatory function of ubiquitin. In viral signaling, we are particularly interested in dissecting the signaling pathway by which a host cell mounts an immune response to RNA virus infection. Lab website
During early development, the embryo acquires its shape and complexity of tissues via the coordination of fundamental cellular processes, such as cell signaling, cell migration, cell adhesion and cell differentiation. During this amazing process, a multitude of different signals must be exchanged between cells at precise times and locations, often in a step-wise manner. We are interested in understanding the molecular mechanisms that underlie organogenesis in the embryo. Understanding these principles will help us to identify and characterize molecular lesions that underlie human birth defects and disease. Lab website
Molecular Immunology focusing on nuclear organization, chromosome territories, transcription factories, chromatin structure, gene rearrangement, transcriptional activation and silencing of the mouse kappa immunoglobulin gene locus, which is 3,200 kb in length. Projects include elucidation of higher-order chromatin structures using capturing chromosome conformation (3C and 4C) and ChIP technology, 3D-DNA/RNA FISH, immuno-FISH, the study of newly discovered regulatory sequences and their binding proteins that inhibit recombination or enhance transcription during B cell development. Cultured mouse cell lines, YAC-based transgenic mice, and BAC-based ES cell knockout technology are being employed for these studies.
The ability to regulate energy homeostasis is a fundamental and fascinating biological process. However, a burgeoning epidemic of obesity and diabetes endangers millions and is altering the landscape of our health care system. We exploit invertebrate and vertebrate model systems to unravel the mechanisms that underlie the formation (stem cells) and function (physiology) of metabolic tissues. The insights obtained from these new approaches should enhance our understanding of metabolic biology and may lead to novel therapeutic targets for obesity and/or diabetes. Lab website
Our laboratory explores the development and function of adult neural stem cells, which are a source of inherent plasticity in the mammalian brain center (hippocampus) critical for learning and memory. We study neural stem cells using a range of novel genetic, cellular, molecular, and imaging methods. A major focus of our lab is to understand the transcriptional/epigenetic regulatory circuitry that guides neural stem cell self-renewal and differentiation in both normal and pathological states. We also explore neuronal cell fate mechanisms using synthetic small-molecules. Lab website
Human nuclear DNA is assembled into repeating macromolecular complexes termed chromatin. The structure of chromatin is tightly regulated by well choreographed actions of multiple elements. Disruption of the normal pattern of chromatin often leads to misregulation of gene expression, a common feature of cancer and other human diseases. The broad interests of my lab are to understand the specific regulatory events that control transcription initiation and elongation in a chromatin context. We will take advantage of combinatorial tools including biochemistry, genetics and genome-wide approaches to dissect the detailed molecular mechanisms. Lab website
The major interest of my lab is the understanding of the molecular events that determine various aspects of animal development. We use the nematode Caenorhabditis elegans as a model system and our research combines genetic, molecular biological, and cell biological approaches as well as advanced imaging technology. Our current research focuses on the following two areas: Regulation of anterior-posterior polarity and cell fate determination during embryogenesis, and genetic and molecular characterization of the oocyte to embryo transition. Lab website
One of the goals of modern developmental biology is to comprehend the molecular and genetic mechanisms that guide the formation of organs during embryogenesis. Our principal interest is to understand the integration of transcriptional and intercellular signaling mechanisms that control organogenesis in mammals.
Our laboratory is interested in mechanisms of post-transcriptional regulation of gene expression and how these pathways influence normal physiology and disease. In particular, we have focused on the regulation and functions of noncoding RNAs with an emphasis on microRNAs (miRNAs). miRNAs are an abundant and diverse family of ~20- to 23-nucleotide RNAs that recognize sites of complementarity in target mRNAs, resulting in decay and reduced translation of target transcripts. miRNAs provide important functions in development and physiology and their aberrant activity is associated with several diseases including cancer. Our work on the miRNA pathway focuses mainly on three broad questions: What functions do miRNAs perform in normal physiologic states? How does aberrant miRNA activity contribute to diseases such as cancer? How is miRNA abundance regulated in normal physiology and disease? Lab website
Our laboratory is focused on the identification and characterization of genes that participate in cancer biology through the use of forward genetics. We employ multiple transposon-based systems to perform insertional mutagenesis in cell culture and in mice for the purpose of identifying novel genes that contribute to tumor cell initiation, progression, and metastasis. These approaches facilitate the discovery of genes and pathways that functionally contribute to tumorigenesis and provide a complementary approach to large-scale cancer genome sequencing studies. Lab website
My lab is interested in elucidating the activity of virulence factors (also called effectors) from pathogenic bacteria so that we can gain novel molecular insight into eukaryotic signaling systems. We study T3SS systems and bacterial effectors to understand how signaling systems in the eukaryotic host can be manipulated by bacterial pathogens. These studies provide novel insight into the molecular workings of eukaryotic signal transduction. Lab website
Necrosis is a process clearly distinguished from apoptosis and is implicated in many human pathological conditions, including infections, ischemic injuries, neurodegeneration, and cancer. However, the molecular mechanisms of necrosis remain largely unknown. Using a combination of chemical genetics and biochemical approaches, our research has brought new insights into necrotic cell death pathways, and identified many chemical inhibitors of necrosis that could lead to therapeutic strategies to treat necrosis-related diseases.
Our research goals are to continue investigating the mechanisms of necrotic cell death, especially the executioners of the process, and ultimately to apply this knowledge to develop novel pharmacological interventions to treat necrosis-related human diseases. Activation of the necrotic pathways in tumors that are highly resistant to apoptosis would be a novel direction in cancer treatment.
Our laboratory is interested in the role of extracellular matrix (ECM) proteins, which provide a tissue- and/or disease-specific microenvironment. We are particularly interested in vascular matrix proteins that are involved in maintenance of the integrity of vessel walls, regulation of intercellular signaling, and modulation of vascular cell phenotype during normal development and disease conditions. We use mouse as a model system and take biochemical, molecular biological and histopathological approaches to study the underlying mechanism of diseases caused by compromised ECM proteins. Lab website
Molecular and cellular biology of postnatal neural stem cells, with a focus on their specification and maintenance. Regeneration of the central nervous system through reprogramming endogenous cells. Molecular signaling in brain tumors. Lab website