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Vascular biology and atherothrombosis

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Diane L. Barber, Ph.D. Professor of Cell & Tissue Biology Research Interests: Signal transduction and Ion xchangers Summary: The research in Diane Barber's laboratory focuses on the regulation and function of two families of plasma membrane ion exchangers, the Na-H exchangers and the Cl-HCO3 exchangers, which regulate intracellular pH. Studies on the regulation of these ion exchangers are designed to investigate the intracellular signaling pathways mediating their activation by hormone and growth factor receptors. Studies on their function are designed to investigate how their regulation of intracellular pH and the actin cytoskeleton contribute to cell growth, differentiation, and migration. One current emphasis is to map GTPase- and kinase-dependent signaling pathways mediating receptor regulation of plasma membrane ion exchangers. To accomplish this we are using two genetic approaches. The first is to express genetically altered alleles in cells to determine the effects on a particular signaling pathway or cellular response. Using this approach, we determined that the Rho family of GTPases plays a predominant role in mediating activation of ion exchangers by hormone and integrin receptors. We also identified specific Rho-regulated kinases that directly phosphorylate and regulate plasma membrane ion exchangers. The second approach we use relies on interaction cloning strategies to identify protein-protein interactions as a means of determining direct regulators and effectors of ion exchangers. These cloning strategies were used to identify novel kinases and calcium-binding proteins that directly associate with plasma membrane ion exchangers. A second current emphasis is to characterize the role of Na-H exchangers in GTPase-dependent cell functions such as proliferation, neoplastic transformation, and migration. We determined that Na-H exchangers regulate these cell functions not only through their well-characterized action on intracellular pH homeostasis, but also through a newly identified action on regulating the organization of the actin cytoskeleton. We found that Na-H exchangers play a critical role in mediating cytoskeletal reorganization by integrin receptors and by the Rho family of GTPases, and that they are structurally linked to the actin-based cytoskeleton through a direct association with actin-binding proteins of the protein 4.1 superfamily. Hence, we have identified a novel function of Na-H exchangers in linking the actin cytoskeleton to the plasma membrane. How this novel function contributes to cytoskeletal organization during integrin- and GTPase-dependent cell contractility and migration is currently being determined. The work in our laboratory is specifically relevant to the CVRI program. We are studying the molecular mechanisms controlling basic cellular processes contributing to cell growth, contractility, and migration. The Na-H exchanger is an important mediator for the inotropic effects of a1-adrenergic agonists, endothelins, and angiotensin II, and its activation is a major mechanism for restoring intracellular pH after acidosis. Influx of extracellular Na+ via this exchanger is a key factor in myocardial pathology associated with ischemia and reperfusion. Additionally, upstream activators of the Na-H exchanger, such as integrins and the GTPase Ga13, regulate the development of the cardiovascular system. Our recent work demonstrating that the Na-H exchanger is critical for cytoskeletal remodeling in response to integrins and Ga13 suggests that its actions on the cytoskeleton may be important for the development and maintenance of cardiovascular functions.

Brian L. Black, Ph.D. Associate Professor of Biochemistry & Biophysics Research Interests: Cardiac and skeletal muscle development, differentiation, and function Summary: Congenital heart anomalies are the most common form of birth defect in the United States, affecting nearly one percent of all babies, yet the molecular and developmental basis for these defects is largely unknown. Tissues and organs form during mammalian embryonic development because of the integration of numerous signaling and transcriptional pathways. Our major goal is to define these pathways in order to understand the molecular causes of congenital anomalies and potential mechanisms for organ regeneration and repair. Using the mouse as a model system, the current work in the lab is focused on defining the pathways regulating the development of cardiac and skeletal muscle, the vascular endothelium, and neural crest. Specific projects focus on the regulation and function of genes that are known to be critical for cardiac development. These include Mef2c, Islet1, Gata4, Bmp4, and Fgf8. Each of these genes is involved in cardiac development, and we are defining their regulation and function specifically during the formation of the cardiac outflow tract, one of the most commonly and severely affected regions of the heart observed in babies. The long-term scientific goal of these studies is to define how tissues and cells are integrated during organogenesis and how cells receive and interpret positional information. We are using a combination of conditional gene knockouts, transgenic reporter assays, and fate mapping techniques in mice to define the embryological origins of the outflow tract and the reciprocal signaling between tissues that is required for proper heart development. The ultimate goal of these studies is to develop diagnostic and therapeutic interventions for birth defects of the heart and other organ systems.

Pao-Tien Chuang, M.D. , Ph.D. Associate Professor of Biochemistry & Biophysics Research Interests: Cell-cell signaling during mammalian development and in postnatal physiology Summary: Our research aims to understand the molecular program that controls mammalian embryonic development, stem cell maintenance and cancer formation. Accumulating evidence indicates a common mechanism underlying these seemingly disparate processes. We have focused on the Hedgehog (Hh) pathway that plays a key role in many aspects of embryonic development and on dysregulation of Hh signaling that is associated with human birth defects and cancers. We use a combination of genetic, cell biological and biochemical approaches to reveal the molecular mechanisms by which Hh signaling controls various essential cellular processes. Our research will lead to a better understanding of mammalian embryonic development, provide insights into stem cell therapy and facilitate drug development for cancer treatment.

Ronald I. Clyman, M.D. Professor of Pediatrics Research Interests: Cardiology, cell biology, developmental biology, neonatology, neonatal cardiology Summary: The ductus arteriosus is a vital fetal blood vessel that diverts blood away from the fetus's lungs and towards the placenta during life inside the uterus. After birth it is essential that the ductus arteriosus constricts and obliterates itself so that the normal postnatal pattern of blood flow can be established. Essentially all full term infants will have closed their ductus by the third day after birth. Preterm infants of less than 30 weeks gestation have a high chance of having a persistently open or patent ductus arteriosus (PDA). If the ductus arteriosus remains open it contributes to the development of several neonatal morbidities: prolonged ventilator dependency, pulmonary hemorrhage, pulmonary edema, chronic lung disease and necrotizing enterocolitis. Our laboratory has been studying the factors that regulate normal closure of the ductus arteriosus in full term infants and abnormal persistent ductal patency in preterm infants. Approaches used to study this problem are: controlled clinical trials, integrated whole animal physiology, in vitro organ culture, and cell biology.

Bruce R. Conklin, M.D. Associate Investigator, Gladstone Institute of Cardiovascular Disease Research Interests: Rewiring G protein signals in vivo Summary: Hormone receptors help to coordinate the development and function of tissues such as the heart. The largest known family of receptors for hormones and drugs are the G proteinÐcoupled receptors, with over 700 human genes. Many of the mostly widely used drugs work on these receptors, so it is of great medical interest to find out how they work. We focus on how these receptors work in embryonic stem (ES) cells, since these cells can develop into beating heart cells in a few days. This way we can rapidly turn on or off receptor signaling pathways, and see what happens in the ES-derived heart cells. Most of our work is with mouse ES cells, but we also work with human ES cells when technically possible. Since many of our experiments produce overwhelming amounts of data we write computer software programs to help analyze these data in the context of known biological pathways. One of our programs is freely distributed (www.GenMAPP.org) and has over 13,000 registered users. For many biologists GenMAPP has become like an ÒAdobe AcrobatÓ for biological pathways, since they can exchange pathway information without buying expensive software. We continue to develop free open-source software to accelerate our own research while helping the community of biologists. In the future, we are particularly interested in designing software to study human genetic variations that could be associated with disease. By combining pathway-oriented bioinformatics with high-throughput experimental methods that probe these pathways, we are gaining insights into the molecular basis for hormonal control of heart development and function.

Shaun R. Coughlin, M.D., Ph.D. Professor of Medicine and Cellular & Molecular Pharmacology; Distinguished Professorship in Cardiovascular Biology & Medicine; CVRI Director Research Interests: Signaling mechanisms in cardiovascular biology and disease, thrombin signaling Summary: How are the thrombi that cause most heart attacks and strokes formed? How is normal blood clotting at a site of tissue injury triggered? Tissue injury initiates the formation of a protease called thrombin at the injury site, and thrombin is the central mediator of blood clotting. Proteases are best known for their ability to cleave or digest other proteins, but some can act like a hormone to trigger specific cellular responses. Indeed, thrombin causes platelets, small specialized blood cells, to aggregate at sites of injury to plug bleeding blood vessels. It is this same process that blocks diseased blood vessels in the heart or brain to cause heart attacks and some strokes. How does a protease like thrombin behave like a hormone to regulate the behavior of platelets and other cells? We've characterized a family of protease-activated receptors (PARs) that provide an answer. PAR1 is the key mediator of thrombin's effect on human platelets. Part of PAR1 is displayed on the outside of the platelet, poised to sense its environment. Thrombin binds to and cleaves this part of PAR1, and this cleavage event triggers a change in the shape of the receptor that sends information across the cell membrane to switch on signaling molecules inside the platelet. PAR1 is the prototype for a family of four related receptors that appear to account for most cellular responses to thrombin and related proteases. Our laboratory currently focuses on understanding the roles of protease and PAR signaling and, more broadly, G protein-coupled receptors in cardiovascular biology. One important line of research uses mice made to lack one or more PARs. Such studies showed that PARs are necessary for platelets to respond to thrombin and for enlargement and propagation of platelet thrombi at sites of blood vessel injury. Interestingly, PAR signaling is unnecessary for formation of initial small juxtamural platelet thrombi, the kind of thrombin that are capable of plugging a small hole in the wall of a small blood vessel but not capable of blocking a major artery. Thus different signaling mechanisms appear to be important at different points in the development of a thrombus and exploiting such differences may permit the development of safer antithrombotic drugs. Specifically, PAR1 blockers may be useful in this regard. Mouse studies have also revealed that proteases and PARs play unexpected roles in the formation of the cardiovascular system and the nervous system in the embryo, roles which we are working to characterize. Lastly, PARs are members of a much larger family of receptors known as G protein-coupled receptors. These receptors regulate a host of physiological processes and it is clear important roles remain to be uncovered. The ~350 G protein-coupled receptors in mice and humans couple through four main G protein families, Gs, Gq, Gi, and G12/13. We are ablating G12/13 and Gi signaling in specific cell types in mice to probe the roles of these pathways in cardiovascular development, metabolism, blood and bone formation, and other important processes, then using a candidate approach to identify the receptors and ligands involved. We expect these studies will point up new strategies for treating diseases of the systems under study.

Rik M. Derynck, Ph.D. Professor of Cell & Tissue Biology Research Interests: Transmembrane TGF-a and TGF-b receptor signaling in cell proliferation and differentiation. Summary: Our research focuses on the role of TGF-a and b, two structurally related growth and differentiation factors, in epithelial and mesenchymal cell proliferation and differentiation. We use various cell biological, molecular and biochemical approaches to address cell physiological and developmental questions. TGF-a is a growth factor for various cell types from ectodermal origin, including most epithelial cells, and exerts its functions in an autocrine and paracrine fashion. TGF-a is normally made as a transmembrane protein at the cell surface and functions in cell communication through its ability to interact with a tyrosine kinase receptor. The ectodomain can be proteolytically released in a highly regulated manner and is then released. Our TGF-a research focuses on the identification and functional characterization of proteins that form a complex in association with transmembrane TGF-a. We study their functions in the presentation of transmembrane TGF-a, signaling and regulation of TGF-aectodomain cleavage in normal and transformed epithelial cells. We are also characterizing the signaling mechanisms that lead to ectodomain cleavage of transmembrane TGF-a and consequent release of soluble TGF-a. TGF-b is a prototype for a large family of growth and differentiation factors which regulate development. TGF-b is also a potent inducer of growth arrest in many cell types. Our research focus is on the mechanism of signaling by TGF-b receptors and its role in mesenchymal differentiation. We study how the Smads, a novel class of intracellular signaling effectors, act as signal transducers following receptor activation, are translocated into the nucleus and regulate gene expression. We also study how this signaling regulates mesenchymal cell differentiation into muscle, bone and fat cells. Finally, we also focus on the characterization of novel signaling pathways, separate from the Smads, that are activated by TGF-b receptors.

Leland G. Dobbs, M.D. Adjunct Professor of Medicine and Pediatrics Research Interests: Pulmonary alveolar epithelial development and response to injury, development of biomarkers for the measurement of lung injury Summary: Our laboratory studies the pulmonary alveolar epithelium. More than 99% of the large internal surface area of the lung (in humans ~100-150 m2) is lined by the alveolar epithelium, which is comprised of type I and type II cells, both of which are thought to be essential for mammalian life. Type I cells are very large squamous cells that cover more than 98% of the internal surface area of the lung, providing a narrow anatomic barrier between the air and blood compartments critical for efficient gas exchange. Type II cells are small cuboidal cells characterized by morphologically distinct secretory organelles, lamellar bodies, which contain the intracellular storage pool of pulmonary surfactant. In vivo, type II cells have the capacity to repair injured alveoli, acquiring at least some characteristics of the type I cell phenotype; under these conditions, they appear to transdifferentiate. Current accepted paradigms are that type I cells play a minimal functional role in the lung, but that type II cells perform major alveolar epithelial functions, including acting as progenitor cells during development and after injury. These paradigms do not adequately explain the results of recent experiments in our laboratory. We have developed novel methods for isolating and studying type I cells, which have previously have been resistant to study. Experiments with both in vitro and in vivo models suggest both a major role for the type I cell in ion and fluid transport and revised paradigms for both alveolar epithelial development and response to injury.

Samuel Hawgood, M.B., B.S., M.D. Professor and Chair of Pediatrics Research Interests: Structure and function of surfactant apoproteins Summary: Our research activity is focused on the biology of the pulmonary alveolus with a particular emphasis on the structure and function of the pulmonary surfactant apoproteins. The human lung is made up of some 500 million alveoli each with a diameter of 200 microns and a septal wall thickness of only 5-8 microns. The large surface area provided by this foam-like architecture is ideal for rapid respiratory gas exchange but necessitates some unique biological answers to the threat to structural stability posed by the problem of high surface tension and the constant exposure to environmental pollutants, allergens and microbes. Pulmonary surfactant, a lipoprotein secretion of the alveolar epithelial type II cell, stabilizes alveolar structure at low transpulmonary pressures by reducing the retractile surface forces that would otherwise act to collapse the lung at end expiration. The surfactant apoproteins also act as components of the pulmonary innate defense system protecting the lung from inflammation and infection. A derangement of alveolar stability, secondary to a developmental deficiency of surfactant, is the major factor in the pathogenesis of the respiratory distress syndrome of the newborn (RDS). My interest in the biology of surfactant grew from clinical experience in neonatology where RDS is a major cause of neonatal death. I moved to UCSF in 1982 as a research fellow with Dr. John Clements, the scientist who discovered surfactant in the late 1950's. He started his own laboratory, focused on the proteins associated with surfactant, in 1984. By 1985 our laboratory had identified three novel surfactant-associated proteins, now known as SP-A, SP-B and SP-C, and had derived their primary structures from full-length cDNA and genomic clones. In 1993, Erica Crouch in St. Louis described a fourth protein, SP-D. The higher-order structure, genetic regulation, metabolism, and function of these proteins have been the focus of our research since that time. We now know that the surfactant proteins have important roles in the activity of surfactant, particularly the ability to rapidly spread phospholipids at the alveolar surface. The proteins also regulate surfactant turnover and metabolism in the alveolus and play a part in non-antibody mediated response to infection and inflammation in the alveolus. The biology of these proteins is complex and they apparently function as interacting hetero-oligomers to mediate their multiple effects on surfactant biology. At least two of the surfactant proteins, SP-B and SP-C, are present in exogenous surfactants approved for clinical use and fatal human disease has been linked to inherited mutations in both these proteins. This clear link to human disease provides a strong rationale to obtain a detailed understanding of their structure and function.

Thomas B. Kornberg, Ph.D. Professor and Vice Chair of Biochemistry & Biophysics Research Interests: Developmental regulation Summary: Our work investigates the genetic and molecular mechanisms that cells use to adopt their assigned fates during development. We focus on one of the striking features of Drosophila development, the process that subdivides each epidermal segment of the insect into an Anterior and a Posterior developmental compartment. The compartment border at the juxtaposition of these two groups of cells has special properties that keep the cells of each compartment separate; it also functions as a signaling center to regulate growth and development of both compartments. Recent progress has identified the genetic network responsible for the generation and function of the compartment border in the Drosophila wing imaginal disc. This genetic network is controlled by the posterior compartment-specific engrailed gene, and it deploys hedgehog (hh) in the posterior compartment and cubitis interrptus (ci), patched and decapentaplegic (dpp) in the anterior compartment. Hh and Dpp proteins function as morphogens to regulate growth and development; current work in the lab is directed to understanding the signal transduction mechanisms that these proteins use. Key recent findings are that post-translational processing of the Ci protein is a pivotal aspect of Hh signal transduction and that imaginal disc cells have thin, actin-based extensions (cytonemes) that project to the signaling center.

Gail R. Martin, Ph.D. Professor of Anatomy Research Interests: Function of the FGF family in early mammalian development; establishment of the vertebrate body plan during gastrulation Summary: The Martin lab is interested in understanding the mechanisms that control the early steps in organogenesis in the vertebrate embryo, and the subsequent outgrowth and patterning of the developing organs. We are particularly interested in the roles played by members of the Fibroblast Growth Factor (FGF) family of signaling molecules and their antagonists in these processes. Our approach to elucidating a particular gene's function is to determine the consequences of perturbing its expression during mouse development. To accomplish this we produce loss- and gain-of-function alleles of the genes of interest and study the consequences of eliminating or increasing their expression in the embryo. Using this approach we have demonstrated that FGF signaling is essential for cell survival during the early development of the brain, kidney, limbs, and other organs. Recently, we have found that eliminating Sprouty gene expression, which essentially increases FGF signaling, has profound effects on the development of the heart and lungs.

Takashi Mikawa, Ph.D. Professor of Anatomy, Camilla and George D. Smith Distinguished Professorship in Science and Medicine Research Interests: Morphogenesis; developmental regulation of organogenesis Summary: Our group investigates the molecular mechanisms involved in the differentiation and patterning of the cardiovascular and central nervous systems. Both organ systems share a common developmental plan to establish their extremely complicated structures and functions: i) construction of a tubular structure from an epithelial sheet along midline body axis, ii) subdivision of the epithelial tube into zones for distinct functional components of the organ, iii) proliferation of cells along a perpendicular axis to the epithelial sheet (clone unit), and iv) cell fate diversification within clone units. Thus, growth of both organs is characterized by the daughter cells from the epithelial sheets proliferating vertically while remaining in close association, thereby generating clone arrays. Three dimensional spherical structures of both the heart and brain are established by the lateral packing of clone units. These findings indicate that each clone is a primary unit for both differentiation and morphogenesis of these organ systems. We are currently analyzing the molecular basis of several of these processes including a) formation of a tubular organ primordium; establishment of the midline identity along which a tubular primordium forms; b) subdivision of neural and non-neural zones during development of the retina (an extension of neural tube); and c) diversification within clone units into the glial and neuronal cell fate (neural retina, optic tectum) and the conversion of myocytes to the impulse conducting cell linage (heart).

Keith E. Mostov, M.D., Ph.D. Professor of Anatomy and Biochemistry & Biophysics Research Interests: Polarized epithelial membrane traffic and epithelial morphogenesis. Summary: How do individual cells organize to form a multicellular tissue? An individual cell can exhibit many different behaviors - proliferation, migration, adhesion, polarization, differentiation, and death. But to build a tissue, a population of cells must coordinate these individual behaviors across space and time. Little is understood about the mechanisms that orchestrate the actions of single cells during morphogenesis. To analyze these issues, we are studying how epithelial cells form three-dimensional organs. Epithelia are coherent sheets of cells that form a barrier between the interior of the body and the outside world. Internal epithelial organs contain two types of building blocks, cysts and tubules. Our experimental strategy uses culture of epithelial cells in a three-dimensional extracellular matrix. Single cells plated in matrix grow to form hollow cysts lined by a monolayer of cells. We have discovered a pathway containing the small GTPase, rac1, alpha1-beta3 integrin, and laminin, which coordinates cell polarity, so that apical surfaces of the cells are all oriented towards the cyst lumen. Cysts are remodeled into by growth factors, which cause transient dedifferentiation and migration, followed by redifferentiation into polarized epithelial cells lining the tubule. Spatial asymmetry is fundamental to the structure and function of most eukaryotic cells. A basic aspect of this polarity is that the cell's plasma membrane is divided into discrete domains. The best studied and simplest example of this occurs in epithelial cells, which line exposed body surfaces. Epithelial cells have an apical surface facing the outside world and a basolateral surface contacting adjacent cells and the underlying connective tissue. These surfaces have completely different compositions. Epithelial cells use two pathways to send proteins to the cell surface. Newly made proteins can travel directly from the trans-Golgi network (TGN) to either the apical or basolateral surface. Alternatively, proteins can be sent to the basolateral surface and then endocytosed and transcytosed to the apical surface. We are studying the machinery that is responsible for the specificity and regulation of polarized membrane traffic in epithelial cells. I will discuss several recent results. 1. The SNARE hypothesis provides a unified model for how intracellular vesicular targeting and fusion work. Proteins on transport vesicles, known as v-SNAREs, pair with corresponding t-SNAREs on target membranes, leading to vesicle fusion. The correct pairing of particular v- and t-SNAREs can provide a mechanism for specificity of targeting and fusion. Polarized epithelial cells are an ideal system in which to test the role of SNAREs in specificity, as these cells contain two plasma membrane targets, the apical and basolateral surfaces, as well as multiple classes of vesicles traveling to each surface. We have found that that the t-SNARE syntaxin 3, is involved with transport to the apical surface, while the related t-SNARE, syntaxin 4, is utilized for transport to the basolateral surface. 2. The polymeric immunoglobulin receptor (pIgR) transcytoses IgA from the basolateral to the apical surface. Transcytosis is stimulated by ligand binding. Binding of IgA causes dimerization of the pIgR, which leads to activation of a non-receptor tyrosine kinase, p62Yes. Mice knocked out for this kinase are deficient in IgA transport. Phosphatidylinositol-specific phospholipase C gamma is activated, resulting in production of DAG and IP3. The DAG activates protein kinase Ce, which stimulates transcytosis. The IP3 raises intracellular free calcium, which also stimulates transcytosis. Stimulation of transcytosis also involves the small GTPase, rab3b, which directly interacts with the pIgR. 3. When epithelial cells, such as MDCK cells, are plated in a 3 dimensional collagen matrix, the cells form hollow, polarized cysts with the apical surface facing the lumen of the cyst. Overexpression of a dominant negative form of the small GTPase, rac, retards lumen formation and leads to a partial reversal of polarity, with the apical surface oriented towards the outside of the cyst. Growth of the cysts laminin rescues this phenotype, indicating that interfering with rac function interferes with the ability of the cell to assemble, laminin, which normally provides a spatial cue. 4. When collagen-grown cysts are stimulated with hepatocyte growth factor (HGF), the cysts develop branching tubules, providing a simple model system for studying tubulogenesis. The exocyst is an eight-subunit complex involved in targeting transport vesicles to specific regions of the plasma membrane. We have found that HGF treatment causes the exocyst to relocalize from the region of the tight junction to the growing tubule, indicating that new membrane is being directed to the tubule. Overexpression a subunit of the exocyst, hSec10, causes the cysts to elaborate an increased umber of tubules, indicating a direct connection between membrane traffic and tubulogenesis.

Charles P. Ordahl, Ph.D. Professor of Anatomy Research Interests: Regulation of gene expression in early embryonic cardiac and skeletal muscle development Summary: Our lab is studying the epigenetic changes that direct embryonic cells to form muscle. Molecular studies have identified protein-DNA interactions that govern gene derepression during myoblast differentiation. Experimental embryological methods have allowed us to identify the place and timing of the decision process in vivo. Our current efforts are directed towards the control of the myoblast decision to differentiate through small molecule pharmacology.

Jeremy F. Reiter, M.D., Ph.D. Assistant Professor Research Interests: How cells communicate with each other. Summary: Eukaryotic cilia and flagella are cellular structures familiar to schoolchildren everywhere for the elegant swath they cut as they propel protozoa through pond water. Less well recognized is the fact that a single immotile cilium is present on almost every type of vertebrate cell. These so-called primary cilia were discovered more than a century ago and, yet, their functions remain largely unexplored. It is now becoming clear that the primary cilium plays important roles in both development and disease. Perhaps its most dramatic function is in the kidney Ð ciliary defects cause polycystic kidney disease, the most common life-threatening monogenic illness. Primary cilia also have roles in sensing environmental information. Photoreceptors and odorant receptors function on primary cilia, and primary cilia are essential for sound reception. Therefore, it is not much of an exaggeration to say that we see, smell and hear through cilia. Our work suggests that cilia also function as critical mediators of intercellular signals during development. One crucial role is in the coordination of the Hedgehog signal transduction pathway. Hedgehog signals are essential regulators of embryonic patterning and cell proliferation, and defects in Hedgehog signaling are important causes of both birth defects and many cancers. We are currently extending this work by asking a few fundamental questions about primary cilia: Do cilia transduce intercellular signals other than Hedgehog? How do cilia interpret signals essential to vertebrate development? Do cilia participate in Hedgehog-mediated oncogenesis? How do cells regulate whether they form a cilium? This work has begun to suggest that the primary cilium is an organelle dedicated to signal transduction, somewhat analogous to a cellular antenna. We hope that our current endeavors will reveal how this antenna interprets the signals required for normal development and homeostasis, and how malfunctions in the antenna contribute to cancer and other important human diseases.

Didier Y. R. Stainier, Ph.D. Professor of Biochemistry & Biophysics Research Interests: Cardiovascular form and function in zebrafish Summary: Our laboratory is interested in understanding mechanisms regulating the development and function of the vertebrate cardiovascular system. To this end, we use the zebrafish because of its embryological and genetic advantages. Specifically, we start by using forward genetics to identify critical regulators of cardiovascular form and function. With the genes in hand, we then start asking more specific questions regarding cell biological and biochemical mechanisms. We have elected to study heart development in the zebrafish, Danio rerio, because it offers unique advantages as a vertebrate genetic system and is also ideal for embryological studies. The zebrafish heart is accessible for continued observation and manipulation at all stages of development and offers single cell resolution of its components. Through several genome-wide screens in zebrafish, we have identified a large number of mutations that affect heart formation and function. We are currently using the tools of cellular and molecular biology, embryology, genetics and advanced microscopy to analyze some of these mutations and further our understanding of the cellular and molecular mechanisms underlying various processes including myocardial differentiation, heart tube formation, endocardial cushion development, endothelial cell differentiation, vasculogenesis, angiogenesis and cardiac function.

Rong Wang, Ph.D. Assistant Professor of Surgery Research Interests: Arteriovenous specification, arteriogenesis, angiogenesis, Notch, blood vessel development, cancer and ischemia Summary: Understanding what controls blood vessel development and identity is an important focus of current biomedical research because of its broad implication in cardiovascular disease, cancer, stroke and many other human diseases. Much of the current research on blood vessel growth, angiogenesis, is centered on capillaries, the small blood vessels that connect the arterial and venous networks. The molecular signals that direct a newly forming vessel to become an artery or a vein are poorly understood. Similarly, the mechanisms responsible for development, maintenance and re-growth of arteries and veins are still largely a mystery. The first genetic component of arteriovenous (AV) specification was recently discovered. During embryonic development, ephrinB2, a cell surface protein, is specifically expressed in the developing arteries. The gene encoding this protein, ephrinB2, is linked to another gene, Notch, which encodes a transmembrane receptor protein, Notch, that is an upstream member of the same signaling pathway. Our laboratory is focused on determining the cellular and molecular mechanisms underlying Notch- and ephrinB2-mediated arterial growth and differentiation. We study Notch- and ephrinB2-mediated arterial growth and differentiation in three contexts: development, cancer and revascularization (development of new blood vessels or expansion of existing blood vessels) following ischemia (stroke). In addition, we look at gain-of-function (protein overexpression) and loss-of-function (gene deletion) mutations. The overall goal of our research is to identify novel drug targets and develop new therapies for cancer, ischemia, peripheral arterial disease, heart attack and stroke, some of the world's most common and devastating diseases.