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Vascular biology and atherothrombosis

Metabolism, obesity and metabolic diseases

Developmental biology and congenital anomalies

Pulmonary biology and disease

Ion channels and arrhythmias

Muscle biology and heart failure

Prediction and prevention of cardiovascular disease

Advanced technologies

Brian L Black, Ph.D. Professor 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 the 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 development diagnostic and therapeutic interventions for birth defects of the heart and other organ systems.

Benoit G Bruneau, B.Sc., Ph.D. Associate Professor Research Interests: Heart development, congenital heart disease, chromatin, embryogenesis, transcription Summary: Our laboratory studies the genes that direct a cell to become a heart cell, focusing on the machinery within each cell that turns genes on or off. Many of these factors are implicated in human congenital heart disease, and our studies also focus on understanding the basis of these diseases.

Pao-Tien Chuang, M.D. , Ph.D. Assoc Professor In Residence Research Interests: Cell-cell signaling during mammalian development and in postnatal physiology Summary: We use mouse as a model system to understand how embryos develop. This knowledge is critical for understanding the basis of human congenital defects. Moreover, many adult diseases have their origin in development. Thus, our studies have important implications for developing stem cell therapy and identifying the cause of cancers.

Ronald I Clyman, M.D. Prof In Rsdn Ped & CVRI 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. Professor In Residence Research Interests: Engineering Hormone Signaling Pathways In Vivo Summary: Hormone receptors direct the development and function of complex tissues, including those found in the cardiovascular system. The focus of our research is on the largest known family of receptors for hormones and drugs, the G proteinÐcoupled receptors. We combine genetic engineering, stem cells and new computer programs to find new treatments of cardiovascular disease.

Shaun R Coughlin, M.D., Ph.D. Professor 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 Research Interests: Transmembrane TGF-a and TGF-b receptor signaling in cell proliferation and differentiation. Summary: Dr. Derynck studies signaling mechanisms that regulate the generation of bone, muscle and fat cells and how these cells derive from mesenchymal stem cells. This knowledge is used to direct mesenchymal stem cells and pre-adipocytes toward the generation of bone and muscle tissues.

Leland G Dobbs, M.D. Adjunct Professor 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. Chair 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.

Julien I Hoffman, M.D., F.R.C.P. Professor Emeritus Research Interests: Pathophysiology of myocardial ischemia Summary: My research investigates the way in which the complex muscular architecture of the human heart functions, and what role different components play in heart failure. Current hypotheses of ventricular architecture emphasize the interaction of spiral and circumferential muscle layers, but one major hypothesis that there is a single folded muscular band is much in dispute. We know that the adult pattern is already complete at 14 weeks gestation, but there is no information about how the primitive cardiac tube becomes this complex multilayered structure. My colleagues and I have shown that different components of this muscle band may be affected in diastolic heart failure, and are seeking further information about how components of the band arise and how each component may be affected by disease. I have ongoing research into the epidemiology of congenital heart disease but no specific problems are being studied at the moment. Most of my previous research involved the control of the regional coronary circulation, with particular reference to the mechanisms of subendocardial ischemia. Although I am not actively working in this field now, I am collaborating with some bioengineers who are studying these problems.

Yuet W Kan, M.D. , D.Sc. Professor Research Interests: The mechanisms of globin production and exploring novel ways of inserting genes into mammalian cells; investigating newer approaches for fetal diagnosis of genetic disorders Summary: Sickle cell anemia and thalassemia are the most common genetic diseases and affect people of African, Mediterranean, Middle Ease and Southeast Asian origins. Our laboratory has pioneered the diagnosis of these conditions by DNA tests and is currently investigating the use of patient specific stem cells for their treatment.

Thomas B Kornberg, B.A., Ph.D. Professor & Vice Chair Research Interests: Developmental regulation Summary: My laboratory investigates the mechanisms that pattern developing organs. We carry out our studies on the fruit fly, as it offers many advantages with its ready accessibility to histological analysis and the ease with which genetic manipulations can be made. We focus on two systems Ð the fly wing and the fly lung. Both are model systems that offer opportunities to identify and characterize basic genetic and molecular mechanisms that are relevant to human development and disease.

Gail R Martin, Ph.D. Professor 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, M.S., Ph.D. Professor In Residence Research Interests: Morphogenesis, development, body axis, patterning, cell-to-cell communication, cell architecture, cell fate diversification, cardiovascular system, cardiac conduction system, central nervous system, haemodynamics, growth factor signaling. Summary: The establishment of extremely complicated structures and functions of our organ systems depends upon orchestrated differentiation and integration of multiple cell types. Our group focuses to explore a common developmental plan for successful organogenesis, by investigating the mechanisms involved in the differentiation and patterning of the cardiovascular and central nervous systems.

Keith E Mostov, M.D., Ph.D. Professor 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.

Jeremy F. Reiter, M.D., Ph.D. Asst Professor in Residence Research Interests: Signaling, primary cilium, stem cell, Hedgehog, Wnt Summary: In the process of development, a single egg cell develops into a complex organism. Understanding how that first cell generates such astonishing complexity is one of biology's great tasks. Not only is this task fundamental to our understanding of ourselves, but it is also critical to understanding the causes of birth defects and other diseases. Many of the mechanisms underlying development depend on intercellular communication, the ability of cells to send and receive information. Secreted signaling proteins can communicate many different types of information, from what type of cell a cell should become to whether a cell should live or die. We are studying the mechanisms by which a cellular organelle, the primary cilium, receives and interprets these signals during development. We are also studying how mistakes in these signals contribute to diseases such as cancer.

David H Rowitch, M.D., Ph.D. Professor Research Interests: Developmental biology, neural tube, CNS cell cycle control and tumorigenesis, cell fate specification, gliogenesis, oligodendrocyte differentiation and myelination, Sonic Hedgehog signaling, transcription factors, Olig bHLH proteins, multiple sclerosis, cerebral palsy, brain cancer. Summary: Dr. Rowitch's laboratory investigates common mechanisms in brain development and neurological diseases such as Multiple Sclerosis and brain cancer. Upon moving to UCSF in 2006, Dr. Rowitch has focused on developing a new translational research program focused on Cerebral Palsy, the leading cause of intellectual disability in the United States.

Nelson B Schiller, M.D. Professor of Cardiology Research Interests: Dr. Schiller specializes in the use of echocardiography in the diagnosis and treatment of heart disease. His research interests center around the quantitation of left ventricular function by quantitative two-dimensional echocardiography and Doppler. Summary: Measuring the heart has been a preoccupation of civilizations since ancient Egypt. Measuring the heart using noninvasive techniques that are free of ionizing radiation has riveted the attention of modern medicine because knowledge of the size of the heart's anatomic parts provides powerful diagnostic and therapeutic information. Dr. Nelson B. Schiller a member of the Department of Medicine, Cardiology Division, CVRI and John J. Sampson-Lucie Stern Endowed Chair in Cardiology, has spent his career investigating the application of echocardiography to the precise measurement and clinical application of the volume, weight and hemodynamics of the chambers and valves of the heart. His work is currently centered on the Heart and Soul Study (Mary Whooley, MD PI), where echocardiography measurements are being related to outcomes of heart disease.

Deepak Srivastava, M.D. Director and Professor Research Interests: Developmental biology, pediatric cardiology, congenital heart defects, organogenesis, human genetics, stem cells, cardiac repair Summary: Dr. Srivastava's work focuses on understanding cardiac development by elucidating the molecular events regulating early and late developmental decisions that instruct progenitor cells to adopt a cardiac cell fate and subsequently fashion a functioning heart. This foundation has been used to discover the genetic basis for some congenital heart malformations.

Didier Y. R. Stainier, Ph.D. Professor Research Interests: Vertebrate organ formation/cardiovascular development/endoderm, liver, pancreas and gut development and regeneration/stem cell differentiation/lipid transport and metabolism Summary: My lab investigates cellular and molecular mechanisms underlying the development, function and regeneration of several vertebrate organ systems including the cardiovascular system. We use the zebrafish to study these questions as this model organism presents several unique advantages including the ability to conduct large-scale screens and is also highly amenable to live imaging.

Rong Wang, Ph.D. Associate Professor in Res Research Interests: Arteriogenesis, Arterial Venous Hierarchy, Arterial Venous Differentiation, Arteriovenous Malformations, Hemodynamics, Biomechanics, Vessel Graft, Collateral Vessel Formation, Vascular Disease, Vascular Imaging, Neovascularization, Angiogenesis Factor, Angiogenesis Inhibitors, Vascular Developmental, Vascular Physiology, Critical Limb Ischemia, Gene Expression Regulation, Tumor Angiogenesis, Hepatocellular Carcinoma, Breast Cancer, Notch, EphrinB2, Vascular Progenitor and Stem Cells, Mouse Genetics, Modeling Vascular Disease, Cell Biology, Molecular Pathogenesis of Vascular Diseases, Vessel Dilation, Microcirculation. Summary: We study arteriogenesis, the radial growth of arteries, which plays a central role in the pathogenesis and treatment of cancer and cardiovascular disease. We use advanced mouse genetics, imaging, cellular, and molecular approaches to identify arteriogenic stimulators in development and disease. Our aim is to uncover novel drug targets and therapeutic interventions to improve human health.

Zena Werb, Ph.D. Professor and Vice Chair Research Interests: Extracellular communication in development and disease Summary: The cellular microenvironment provides cells with information essential for controling development , cell-specific fate determination, gain or loss of tissue-specific functions, cell migrations, tissue repair and cell death. We are studying the role of the microenvironment in controlling embryonic development, mammary gland and bone development and tumorigenesis. Our interests include the critical roles that the ECM, inflammatoryand innate immune cells, vascular development and angiogenesis and degradative enzymes such as the matrix metalloproteinases play in these processes. We are taking genetic and molecular approaches to determine the identity and function of the critical molecules, how their expression and activities are regulated, what the molecular and cellular targets of these genes are, and how these regulate the signaling pathways. We are studying how a developing vascular system regulates bone formation, breast development and tumor growth. For example, we have found that tumor cells metastasize in regions of the tumor where blood vessels are abnormal and where there are abundant inflammatory cells. We want to understand the temporal, spatial and causal relationship between these three compartments, and whether targeting the tumors cells, blood vessels or the inflammatory cells, or all of them can slow down metastasis.

William L Young, M.D. Professor/Vice Chair Research Interests: Integrative physiology of the cerebral circulation with special reference to cerebral vascular malformations and occlusive cerebrovascular disease; angiogenesis-related aspects of cerebral hemorrhagic disease; clinical physiology of systemic and cerebral circulatory manipulation during neuroanesthetic management Summary: Few effective therapies are available for stroke. Better understanding of how the formation of new blood vessels in a damaged brain contributes to recovery from injury is an important area of interest. An important subtype of stroke is rupture of abnormal blood vessels (arteriovenous malformations or aneurysms). Better understanding of how these diseases begin and progress will lead to more effective therapies.