Fielding, Christopher J

Pittet, Jean-Francois

Stainier, Didier Y. R.

CVRI Scientists

Kaveh Ashrafi, Ph.D.
Assistant Professor

Research Interests:
Genetics of fat regulation and neurobiology of feeding behavior

Summary:
Obesity is a major risk factor associated with many diseases including diabetes, cardiovascular and gastrointestinal diseases, arthritis, and certain forms of cancers. The prevalence of obesity reflects the combination of high calorie diets with sedentary lifestyles. However, genetic predispositions play profound roles in determination of an individual's fat. How genetic and environmental factor interact to determine fat content and how excess fat accumulation causes disease processes are poorly understood. To identify genes that underlie fat regulation we use the genetically tractable worm C. elegans. This system has allowed us to discover novel fat regulatory pathways, compounds that alter fat content, and probe the neural circuits that regulate fat and feeding.

Harold S. Bernstein, M.D., Ph.D.
Professor in Residence, Pediatrics

Research Interests:
Stem cells, cardiac muscle, skeletal muscle, cell cycle regulation

Summary:
Each year, more than 900,000 people in the U.S. experience a heart attack, and about 500,000 die from complications of heart failure. Heart failure occurs when heart muscle cells are damaged and the heart is unable to meet the demands placed on it by the body. Unlike other organs, the heart is unable to repair itself. We seek to develop new ways of stimulating heart muscle repair or producing replacement heart muscle cells to be used for repair, thereby treating or avoiding heart failure.

Specifically, our laboratory studies the mechanisms regulating cell division, and how such processes play a role in cardiovascular biology and disease. To this end our work has focused on three main areas of basic investigation: 1) mechanisms of cell cycle withdrawal during muscle differentiation; 2) cardiac fate determination in myogenic stem cells, and; 3) the role of cell cycle machinery in cellular hypertrophy. In addition, we recently have initiated two new areas of translational and clinical research that apply their understanding of how muscle cells behave to the development of new diagnostic and therapeutic approaches to heart failure: 4) human embryonic stem cell-based therapies for heart failure; and 5) identification of biomarkers of heart failure in patients with congenital heart disease.

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.

Paul D Blanc, M.D., MSPH
Division Chief

Research Interests:
Epidemiology of occupational lung disease, Asthma outcomes and Occupational toxicology

Summary:
Dr. Blanc's research addresses the impact of work-related and environmental exposures on human health, in particular respiratory diseases such as asthma, and COPD. His work focuses on the role that such exposures can play in causing disease and also how ongoing stressors can aggravate pre-existing disease and lead to disability

Elias H Botvinick, M.D.
Professor In Residence

Research Interests:
Nuclear medicine, nuclear cardiology, PET/CT, MRI, CT, cardiac cardiology, echocardiology, nuclear magnetic resonance, cardiovascular imaging, stress testimg, heart, myocardial perfusion, scintigraphy, coronary, sychrony, sychronization

Summary:
My research centers on a collaborative effort to develop noninvasive imaging methods for the identification and evaluation of cardiac anatomy and pathophysiology, and apply them to the diagnosis, risk stratification and monitoring of clinical disease. The work is centered on nuclear medicine methods, PET and SPECT, as well as echocardiography, MRI, and CT.

Homer A Boushey, M.D.
Prof & Chief

Research Interests:
Bronchial hyperreactivity in asthma. Effects of viral infection on airway function. Regulation of airway mucous secretion and vascular permeability.

Summary:
Dr. Boushey's goal is to develop ways of curing and preventing asthma. His research takes advantage of new methods for detecting viruses and bacteria to examine relationships among the allergens and bacteria found in the environment, bacteria in the gastrointestinal tract, the function of the immune system, and the development of asthma.

V Courtney Broaddus, M.D.
Professor

Research Interests:
Role of apoptosis in asbestos-induced malignancy. Molecular interaction of asbestos fibers with mesothelial cells, specifically with regard to the role of cell surface adhesion receptors.

Summary:
Our lab studies the ways that tumor cells resist dying either when they are single cells or when they aggregate into clumps, called 3-dimensional spheroids. Our goal is to understand the strategies that resistant tumors use to avoid death and then find ways to bypass these defenses.

Frances M Brodsky, B.A., D. Phil.
Professor

Research Interests:
REGULATION AND FUNCTION OF CLATHRIN-MEDIATED MEMBRANE TRAFFIC

Summary:
Critical pathways of human nutrition are controlled by clathrin proteins that are present inside cells. Clathrins control uptake of cholesterol from the bloodstream and uptake of glucose into skeletal muscle, processes that influence heart disease and diabetes. The laboratory focuses on understanding molecular aspects of clathrin function for insight into cardiovascular disease.

James K Brown, M.D.
Assoc Prof In Rsdn & Dir

Research Interests:
Protease signaling

Summary:
In asthma, abnormal growth of airway smooth muscle cells contributes to difficult breathing. Mast cells are a prominent inflammatory cell in the airways of these patients, and during allergic reactions, mast cells release a substance called tryptase. Our work focuses on understanding how tryptase activates smooth muscle cells to grow.

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.

George H Caughey, M.D.
Professor In Residence

Research Interests:
Regulation of lung and airway function by mast cell, leukocyte and epithelial proteases

Summary:
The Caughey lab is interested in understanding how protein-cleaving enzymes of mast cells, white blood cells, and cells lining the airway contribute to inflammation, host defense, tissue remodeling and barrier function in the lung. These studies relate to clinical problems in asthma, cystic fibrosis, lung transplantation and pneumonia.

Harold A Chapman, M.D.
Professor

Research Interests:
Antigen presentation by MHC class II molecules important to immunity and autoimmunity and extracellular matrix remodeling important to cell migration and tissue repair

Summary:
The Chapman lab is focused on basic and biomedical aspects of lung injury and tissue remodeling. Currently the lab is exploring the process of epithelial to mesenchymal transition (EMT) in the lung, a process whereby epithelial lining cells of the lung become reprogrammed to migrate and activate a fibrotic program. The process is also implicated in progression of lung cancer and the lab is exploring the mechanisms by which EMT contributes to lung fibrosis and cancer metastasis.

Israel F Charo, M.D. , Ph.D.
Professor In-Residence

Research Interests:
Structure and Function of Chemokine Receptors

Summary:
The goal of our research is to use gene targeting and creation of transgenic mice to study the in vivo functions of chemokines and chemokine receptors. Chemokines are proinflammatory cytokines that function in leukocyte chemoattraction and activation and block HIVÐ1 infection of target cells through interactions with chemokine receptors. In addition to their function in viral disease, chemokines have been implicated in the pathogenesis of atherosclerosis, glomerulonephritis, and inflammatory lung disease. The chemokine family is growing rapidly. Our laboratory focuses primarily on two chemokines: monocyte chemoattractant protein 1 (MCP-1) and fractalkine, a recently described and structurally unique chemokine.

Kanu Chatterjee, M.D.
Professor

Research Interests:
Diagnosing and managing coronary artery disease, heart failure and pulmonary hypertension.

Summary:
Cardiologist Dr. Kanu Chatterjee has more than 30 years of experience in diagnosing and managing coronary artery disease, heart failure and pulmonary hypertension. He is a world-renowned researcher in vascular reactivity and heart failure and has pioneered the study of drugs, such as ACE inhibitors and vasodilators, that have become the standard of care for heart failure.

He serves on advisory boards for pulmonary hypertension study designs and on data, safety and monitoring committees for multi-center trials of pulmonary hypertension treatments. Certified in internal medicine and cardiovascular disease, he is on the editorial boards of professional journals in cardiology. He was director of the Inpatient Cardiology Service at Cedars-Sinai Medical Center in Los Angeles before joining the UCSF Medical Center staff in 1975 as director of the Cardiac Care Unit and associate chief of Cardiology. He is the Ernest Gallo Distinguished Professor of Medicine at the University of California at San Francisco. A research center at UCSF, called the Chatterjee Center for Cardiac Research, was named after him.

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.

Michael S Conte, M.D.
Chief, Vascular Surgery

Research Interests:
Aortic reconstruction, carotid artery disease, lower extremity arterial occlusive disease, diabetic vascular disease

Summary:
Our laboratory studies the healing process in blood vessels which currently limits the long term success of procedures like angioplasty and bypass surgery. Our goals are to develop new drug and molecular therapies to prevent failures due to vessel re-narrowing, and to better identify patients at increased risk.

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.

Mark D Eisner, A.B., M.D. , M.P.H.
Assoc Professor In Residence

Research Interests:
Epidemiology and health outcomes of obstructive lung disease Key words: asthma, COPD, epidemiology, indoor air pollution, environmental tobacco smoke, secondhand smoke, passive smoking, disability, severe asthma, health outcomes

Summary:
The burden of obstructive lung disease, which includes asthma and Chronic Obstructive Pulmonary Disease (COPD), continues to increase in the U.S. and around the world. My research program in obstructive lung disease has two central areas: (1) to identify factors that negatively affect the health of adults with asthma, especially those with severe disease and (2) to elucidate how disability develops in COPD. These two parallel lines of investigation are distinct, but mutually reinforcing. In asthma, I am studying how smoking, secondhand smoke exposure, and other environmental exposures affect the health outcomes of adults with asthma. I am also interested in how the process of health care, which includes specialist care, influences health among adult asthmatics. In addition, I am studying how patient-level factors, such as depression and quality of life, impact asthma-related health.

A central goal of my research in obstructive lung disease is to prevent deterioration of health status and the development of disability. In a large cohort of patients with COPD, I will elucidate the disablement process in COPD. I have previously shown that adults with COPD have a 10-fold higher risk of disability than members of the general population. However, the current understanding of how disability develops in COPD is limited. In particular, pulmonary function impairment and clinical staging systems do not predict who will develop disability. To elucidate the disablement process, I have established a population-based prospective cohort study of 1200 COPD patients to test a specific conceptual model of how disability develops in COPD. The goal is to provide a scientific basis for the screening and prevention of COPD-related disability.

Joanne N Engel, M.D., Ph.D.
Prof In Residence

Research Interests:
Bacterial Pathogen-Host Cell Interactions

Summary:
My laboratory is interested understanding and exploiting the complex interplay of microbial pathogens with eukaryotic cells. To that end, we have investigated the key processes of microbial attachment and entry, intracellular survival, and host cell injury in the context of two important human pathogens, Pseudomonas aeruginosa (PA) and Chlamydia trachomatis (CT). Each of these microorganisms has developed a unique strategy for successful survival that involves subverting and exploiting host cell pathways. Dissecting these processes will allow the development of new diagnostics, therapeutics, and vaccines and will provide a unique window into eukaryotic cell biology.

David J Erle, M.D.
Professor of Medicine In Resid

Research Interests:
Asthma, allergy and inflammation; functional genomics

Summary:
Asthma is an increasingly common disease that affects about 20 million American children and adults. We are working to understand how proteins made by the immune system act within the lungs to cause some of the most important problems experienced by people with asthma. We also work on understanding newly discovered ways in which genes are turned on and off during health and disease.

John Vincent Fahy, M.D.
Professor In Residence

Research Interests:
Mechanism oriented studies of airway disease in human subjects

Summary:
Our research involves studies in people with airway diseases such as asthma, cystic fibrosis, and chronic bronchitis. We are involved in clinical trials of new and established treatments on the one hand and in clinical studies designed to improve understanding of mechanism of disease on the other. For clinical trials, we often collaborate with other CVRI investigators or investigators at other institutions to compare the efficacy of new and established drugs. In conducting clinical trials, we are usually interested in exploring the effects of drugs not just on measures of lung function but also on measures of airway inflammation and remodeling. For this purpose, our laboratory has developed expertise in measuring markers of inflammation and remodeling in samples of sputum or in samples of airway fluids and tissue collected during bronchoscopy. Our lab is particularly experienced in measuring gene expression using gene chips and PCR and in quantifying pathology using a rigorous method of quantitative morphology called stereology.

For our research on mechanisms of airway disease, we are particularly interested in abnormalities of airway epithelial cells (the lining cells of the airway) and in abnormalities in airway mucus. Mucus abnormalities are common in lung diseases, and we are interested in finding out the specific mucus abnormalities that are characteristic of different lung diseases such as asthma and cystic fibrosis. Recently, we have begun to explore the physical properties of airway mucus - thickness, stickiness, and adhesiveness - using an instrument called a rheometer. The rheology of airway mucus has not been investigated in detail, but the research resources of the CVRI are well suited to making progress in this area. For example, in our clinical laboratories in the CVRI, we can collect induced sputum from volunteers in a carefully controlled way, and in our bench laboratories we can make careful rheological measures. These rheologic measures are allowing personnel in our lab to explore new strategies for breaking up the mucus that normally clogs airways.

Robert V Farese, M.D.
Professor In Residence

Research Interests:
Cell Biology of Energy Metabolism

Summary:
Dr. Farese is an expert on the biology of obesity. His work over the past 15 years has focused on energy and fat metabolism. Using a variety of organisms, such as yeast and mice, his group identified and determined the functions of many of the enzymes of fat synthesis. They identified many of the genes that regulate fat storage in cells. His work has broad implications for cell biology, the understanding of complex diseases such as type 2 diabetes, and the development of biofuels.

Dr. Farese recently shifted a part of his laboratory's interest to studying neurobiology and neurodegenerative disease, particularly frontotemporal dementia (FTD). He is currently co-director of a new effort, the Consortium for FTD Research (CFR) to study the biology of FTD and develop cures.

Christopher J Fielding, Ph.D.
Professor

Research Interests:
Cholesterol, high density lipoprotein (HDL), caveolae, signaling, lipid-binding, atherosclerosis, cholesterol-binding proteins, plasma membrane

Summary:
The research in our laboratory deals with the formation, activity and turnover of high density lipoprotein (HDL), the 'good cholesterol' component of plasma lipoproteins. HDL lowers peripheral cell cholesterol levels by promoting cholesterol transport to the liver. It regulates signaling across cell membranes by controlling the cholesterol content of lipid rafts and caveolae, cell surface complexes of signaling proteins. Finally, HDL opposes inflammation when it acts as a scaffold for enzymes that bind and break down oxidized lipids to harmless by-products. Low HDL is a strong indicator of increased risk for human atherosclerotic heart disease. The development of HDL-raising drugs has recently accelerated. Our ability to raise plasma HDL levels will depend on defining the molecular mechanisms by which HDL is formed and recycled.

Jeffrey R Fineman, M.D.
Professor in Residence

Research Interests:
Endothelial regulation of the pulmonary circulation during normal development and during the development of pediatric pulmonary hypertension disorders. Endothelial dysfunction in pediatric pulmonary hypertension

Summary:
Pulmonary hypertension, high blood pressure in the lungs, is a serious disorder in subsets of neonates, infants, and children. These include newborns with persistent pulmonary hypertension of the newborn (PPHN), children with congenital heart defects, and teenagers and young adults with primary pulmonary hypertension. The vascular endothelium (the cells that line the blood vessels in the lungs), via the production of vasoactive factors such as nitric oxide and endothelin-1, are important regulators of the tone and growth of pulmonary blood vessels. We utilize an integrated physiologic, biochemical, molecular, and anatomic approach, to study the potential role of aberrant endothelial function in the pathophysiology of pulmonary hypertensive disorders. To this end, we utilize fetal surgical techniques to create animal models of congenital heart disease, and investigate the early role of endothelial alterations in the pathophysiology of pulmonary hypertension secondary to congenital heart disease with increased pulmonary blood flow. Our clinical research interests include the use of pulmonary vasodilator therapy for pediatric pulmonary hypertension, and the use of peri-operative BNP levels as marker of outcome following repair of congenital heart disease.

David G Gardner, M.D.
Professor in Residence

Research Interests:
Cardiovascular endocrinology, natriuretic peptides, natriuretic peptide receptors, vitamin D, nuclear hormone receptors, growth and hypertrophy in cardiovascular system and kidney, obesity-related cardiomyopathy.

Summary:
Our laboratory is interested in understanding the role that hormones play in the control of growth and function in the cardiovascular system (heart and blood vessels). We are particularly interested in vitamin D and the natriuretic peptide hormones, two classes of hormones that have beneficial effects on cardiovascular function.

Zev Jordan Gartner, M.S. , Ph.D.
Acting Assistant Professor

Research Interests:

Summary:
We use RNA and DNA, a cell's molecular information carriers, as structural components to build and perturb living systems.

Stanton A Glantz, Ph.D.
Professor of Medicine

Research Interests:
Mechanics of cardiac function (experimental and theoretical); environmental tobacco smoke and tobacco control policy

Summary:
Dr Glantz studies the effectiveness of different tobacco control strategies, particularly in the context of large state-run tobacco control programs, how the tobacco industry works to systematically distort the scientific process and animal and human studies of the effects of passive smoking on the heart.

Warren M Gold, B.A., M.D.
Professor

Research Interests:
Pulmonary physiology, exercise physiology, pulmonary vascular obstruction, early diagnosis, dyspnea, asthma, COPD, diffusing capacity.

Summary:

Michael Gropper, M.D., Ph.D.
Professor In Residence

Research Interests:
Transfusion related acute lung injury, acute respiratory failure, acute respiratory distress syndrome, sepsis, ventilator associated pneumonia, resuscitation, mechanical ventilation, critical care outcomes

Summary:
My research interests are all focused on improving outcomes in critically ill patients in the ICU. These interests range from basic scientific questions regarding the mechanisms of harm from blood transfusions to asking about whether we efficiently utilize our precious resources, particularly at the end of life.

William Grossman, M.D.
Division Chief

Research Interests:
Diastolic function of the left ventricle

Summary:
Dr. William Grossman has been a pioneer in research on diastolic function of the left ventricle and is editor of the widely respected textbook, "Grossman's Cardiac Catheterization, Angiography and Intervention,: which is used by cardiology trainees around the world. Grossman is the Meyer Friedman Distinguished Professor of Medicine at UCSF and chief of the Cardiology Division at UCSF Medical Center.

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.

Arthur C Hill, M.D.
Prof of Clinical Surgery

Research Interests:
Vascular biology, biomimetics, and New Technology in Cardiovascular Surgery.

Summary:
Arthur Hill is a member of the Faculty, Depatment of Surgery, Division of Caridiovascular Surgery, at the University of California, San Francisco. Dr. Hill did a Post-Graduate Research Fellowship at the Cardiovascular Research Institute at UCSF. Clinical training included General Surgery Residency at UCLA, Cardiothoracic Surgery Fellowship at Stanford University, Heart and Lung Transplant Fellowship at Stanford University, and Associate Staff Fellowship at the Cleveland Clinic. Clinical interests include adult Coronary Revascularization, Aortic Surgery, Mitral Valve Repair, Minimally Invasive Cardiac Surgery, and non-Cardiac Thoracic Surgery (including surgery for MDRTB). Research interests include vascular biology, biomimetics, and New Technology in Cardiovascular Surgery.

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.

Holly A Ingraham, Ph.D.
Professor

Research Interests:

Summary:
Our research is focused on development of endocrine and brain regions that contribute to energy balance and reproduction. We concentrate on NR5A nuclear hormone receptors that specify cell fate in developing endocrine organs and the hypothalamus using structural biology, biochemistry and physiology.

Lily Y Jan, B.Sc., M.Sc., Ph.D.
Professor

Research Interests:
Studies of potassium channels

Summary:
Ion channels such as potassium channels and calcium-activated chloride channels are important for the function of the heart, lung, and vasculature. Starting with molecular characterizations of the channel proteins, we try to understand how these channels work and how their activities are regulated under various physiological conditions

David J Julius, S.B., Ph.D.
Chair and Professor

Research Interests:

Summary:

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.

John P Kane, M.S., M.D., Ph.D.
Prof

Research Interests:
Structure and function of lipoproteins; genetic determinants of arteriosclerosis

Summary:
The Kane laboratory focuses on the discovery of the native structures of lipoproteins ( proteins that carry cholesterol so that we can better understand how they are involved in the development of heart disease and stroke. We are also active in the discovery of alterations in genes that lead to heart disease and stroke.

Joel S Karliner, A.B., M.D.
Prof of Medicine Emeritus

Research Interests:
Cardioprotection

Summary:
Our lab is devoted to studying cardioprotection. We employ isolated cells and hearts subjected to oxygen deprivation that simulate a heart attack. We then use promising drugs that salvage heart muscle during and after a heart attack, confirm that they are efficacious, and then study their mechanism of action.

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.

Theodore W Kurtz, M.D.
Prof in Res & Vice Chair

Research Interests:
Molecular Genetics of Complex Disease, Genetic Models of Hypertension and the Metabolic Syndrome, Transcription Modulating Drugs

Summary:
Hypertension affects 30% of the population and is a major cause of stroke, kidney failure, and heart disease. Patients with hypertension are also at increased risk for diabetes. Our laboratory is studying genetic mechanisms that promote increased blood pressure with the goal of identifying new opportunities for the prevention and treatment of hypertension, diabetes, and cardiovascular disease.

Pui-Yan Kwok, M.D., Ph.D.
Professor In Residence

Research Interests:
Genetic analysis of complex traits, DNA technology development

Summary:
We are developing efficient methods to analyze single DNA molecules and applying molecular genetic tools to identify genetic factors associated with complex human traits such as longevity, sudden cardiac arrest, stroke, psoriasis, lupus, and kidney transplantation outcome. We are also conducting studies to identify genetic factors associated with drug response. The overall goal of our research is to develop the tools for genetic analysis of whole genomes and apply these tools to elucidate the genetic factors associated with common human diseases and phenotypes. The sequencing of the human genome and the mapping of common genetic variation by the International HapMap Consortium, in which our lab participated, have inspired an explosion of new technologies, accelerating identification of genetic susceptibility loci. Our phenotypes of interest include kidney transplantation outcomes, longevity, pharmacogenetics of membrane transporters, sudden cardiac death, psoriasis, skin cancer and brian vascular malformations and hemorrhage.

Stephen C Lazarus, M.D.
Professor of Clinical Medicine

Research Interests:
Role of inflammation in asthma and COPD, mucus hypersecretion.

Summary:
Asthma affects 5-10% of the US population, and deaths from asthma have increased for several decades. COPD is the 4th leading cause of death in the US. Understanding the mechanisms involved in these diseases and how best to treat them will contribute to better outcomes.

Randall J Lee, M.D., Ph.D.
Prof of Clin Med

Research Interests:
Arrhythmias, radiofrequency catheter ablation, implantable cardioverter/defibrillators, genetics, gene therapy, tissue engineering, stem cells, cell transplantation, biopolymers, antibodies, myocardial reconstruction/regeneration

Summary:
The research program integrates the disciplines of cell biology, bioengineering and cardiology. A tissue engineering approach is being used to investigate the potential application of cardiovascular reconstruction/regeneration. The use of stem cells and engineered polymer scaffolds are being investigated in heart attach models to determine their usefulness and safety in repairing damaged heart tissue.

Wendell A Lim, Ph.D.
Professor

Research Interests:
Signal transduction, synthetic biology, systems biology, structural biology, protein-protein interactions, cell motility, MAP kinase cascades, GTPase pathways

Summary:
Wendell Lim's Lab is working on creating a detailed instruction manual - a sort of user's guide - that explains how biochemical circuits control a cell's function and ultimately its fate. The long-term goal is to use the instruction manual to help scientists design cells to deliver therapeutic payloads, repair cancerous lesions, or attack microscopic pathogens. Cells are complex mechanical and sensing devices that can carry out highly complex tasks, such as secreting antibodies or forming repair structures like blood clots and bone. Cells contain signaling pathways that take in and integrate vast amounts of information about the cells' environment, and they process and use this information to make complex decisions about how to respond to changing environmental conditions. If more is understood about how these processes work, there is the potential to change cells and help solve problems in biotechnology or health, and to treat disease more rationally.

Robert W Mahley, B.S., Ph.D., M.D.
Director

Research Interests:
I. Plasma lipoprotein metabolism ¥ Hepatic and intestinal origin of plasma lipoproteins; ¥ Apolipoprotein structure and function, especially apolipoprotein (apo) E and apoB; ¥ Characterization of cell surface receptors for lipoproteins; ¥ Role of the liver in cholesterol homeostasis. II. Relationship of plasma lipoproteins to the development and progression of atherosclerosis ¥ Role of diet in progression of coronary artery heart disease; ¥ Effect of apoE production in the artery wall on inhibition of atherogenesis. III. Role of apoE in the nervous system ¥ Effect on peripheral nerve injury and repair; ¥ Role in the pathogenesis of Alzheimer's disease; ¥ Effect on neuronal cytoskeleton. IV. Turkish Heart Study ¥ Director of epidemiological study to determine the risk factors responsible for coronary artery disease in Turkey; ¥ Characterization of genetic polymorphisms responsible for low HDL-C levels and metabolic syndrome in Turks; ¥ Co-director of physician continuing education program for Turkish doctors and medical students in the area of cardiovascular disease.

Summary:
My research has focused on the structure and function of apolipoprotein (apo) E, specifically its critical role in cholesterol homeostasis and atherosclerosis and, more recently, in Alzheimer's disease and neurodegeneration. ApoE regulates the clearance of plasma lipoproteins by mediating their binding to lipoprotein receptors and is also involved in peripheral nerve regeneration, lipid transport in the nervous system, and cytoskeletal stability and neurite extension and remodeling. A goal of our research is to develop a drug that will block the detrimental effects of apoE4 in cardiovascular and neurodegenerative disorders.

Mary J. Malloy, M.D.
Senate Emeritus

Research Interests:
Molecular mechanisms in lipoprotein metabolism; genetic basis of metabolic disorders of lipoproteins and of arteriosclerosis

Summary:
My chief research foci are the discovery of previously unknown disorders that affect the metabolism of cholesterol and other lipids, and the discovery of genes that are associated with the risk of heart attack and stroke. Identification of these diseases and genetic markers of risk will lead to improved prevention and treatment of coronary disease and stroke.

Michael J Mann, M.D.

Research Interests:
1. Molecular/cellular biology and molecular genetics of atherosclerosis and heart failure. 2. Development of hybrid surgical and molecular/cellular therapies for heart disease. 3. Stem and progenitor cell transplantation for cardiovascular regeneration. 4. Cardiovascular tissue engineering. 5. Reduction to clinical practice of current methods in genetic, molecular and cellular disease intervention. 6. Novel targeted molecular therapies for lung cancer. 7. Molecular profiling of cancers for personalized medicine. 8. Development of novel methods of in vivo/ex vivo gene therapy and gene transfer. 9. Novel approaches to therapeutic neovascularization for coronary and peripheral ischemic disease. 10. Cardiovascular cell cycle biology. 11. Myocardial gene therapy.

Summary:
Dr. Mann's research focuses on the molecular and cellular biology of heart disease with an emphasis on practical ways to develop new treatments for heart failure. These involve potential gene and molecular therapies, combinations of molecular and cell-based treatments with surgical reconstruction, and evaluation of novel materials for the development of bioartificial replacements of lost or damaged heart tissue.

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.

Michael A Matthay, M.D.
Professor In Residence

Research Interests:
Alveolar epithelial transport under normal and pathologic conditions. Resolution of pulmonary edema Mechanisms of Acute Lung Injury

Summary:
My research program is focused on identifying mechanisms responsible for fluid transport across the alveolar epithelium using cell, molecular, and in vivo models. In addition, our group is focused on understanding the mechanisms responsible for the development and resolution of pulmonary edema and acute lung injury in critically ill patients with acute respiratory failure. The studies include experimental and human-based studies designed to understand the pathogenesis of acute respiratory failure and to test potential new therapies. The work is supported primarily by grants from the National Heart, Lung, and Blood Institute.

Donald M Mcdonald, M.D., Ph.D.
Professor

Research Interests:
Angiogenesis; cancer; chronic inflammation; endothelial cells; vascular remodeling

Summary:
Our laboratory is studying the cellular mechanisms of angiogenesis, vascular remodeling, and plasma leakage in mouse models of chronic inflammation and cancer. We are also studying cellular changes in lymphatic vessels in disease models. The goal is use novel in vivo cell biological approaches to identify abnormalities of blood and lymphatic vasculature that can serve as the basis of novel treatments. In one area of research, we are examining the mechanism of the action of VEGF, angiopoietins, and other factors on blood vessel growth, remodeling, and leakiness. Other experiments include exploring the mechanism and reversibility of vascular remodeling and angiogenesis and examining the cellular actions of inhibitors of angiogenesis and lymphangiogenesis in tumors and inflammatory disease. We are also studying the cellular mechanisms of plasma leakage in disease. Here, the mechanism of plasma leakage from tumor vessels, due to a defective endothelial monolayer, contrasts with leakage in inflammation, where intercellular gaps form in seconds and reseal spontaneously. Multiple different disease models in wild-type, transgenic, and knockout mice are being used in combination with novel therapeutic agents to identify the cells and growth factors that drive angiogenesis and vascular remodeling and to understand the mechanism of reversibility of vascular changes in inflammation and cancer.

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.

Daniel L Minor, Ph.D.
Associate Professor

Research Interests:
Membrane proteins; potassium channels, calcium channels

Summary:
Hearts, brains, muscles, and senses require electrical signals to function. We aim to understand the basic cellular components responsible for generating electrical activity. We focus on understanding the structure, function, and regulation of ion channels from a high-resolution viewpoint, understanding how channel mutations cause disease, and on developing new tools for controlling channel function.

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.

Jay A Nadel, M.D.
Professor

Research Interests:
Signaling mechanisms in airway epithelium

Summary:
Lungs defend the host against inhaled 'invaders' such as bacteria and viruses and eliminate the invaders efficiently without symptoms. However, abnormal or exaggerated host responses lead to diseases such as asthma, cigarette smoke-induced airway obstruction (COPD), and cystic fibrosis (CF). Our studies have led to the development of novel therapies.

Jeffrey E Olgin, M.D.
Professor In Residence

Research Interests:
Cardiac Electrophysiology, Arrhythmias, Mechanisms, Remodeling, Cardiac Fibrosis, Atrial Fibrillation, Cardiac Ablation, Mouse models, animal models, mouse electrophysiology, optical mapping, atrial fibrillation ablation, clinical trials.

Summary:

David Pearce, B.A., M.D.
Professor of Medicine

Research Interests:
Epithelial biology as it relates to cardiovasculare function: hypertension, fluid and electrolyte regulation.

Summary:

Jean-Francois Pittet, M.D.
Professor In Residence

Research Interests:
Molecular mechanisms of acute lung injury; molecular mechanisms of coagulation derangements after severe trauma.

Summary:

Rita F Redberg, M.D., M.Sc.
Professor

Research Interests:

Summary:
Dr. Rita F. Redberg's research interests are non-invasive imaging of the coronary arteries comparing transesophageal echo with ultrafast CT and magnetic resonance imaging. Her ongoing research studies include a stray of the role of exercise in heart disease in women. She also does research in exercise echo evaluation of valvular and congenital heart disease as well as the use of transesophageal echo imaging in cardiopulmonary resuscitation.

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.

Steven D Rosen, Ph.D.
Professor

Research Interests:
Sulfated Sugars in Biological Processes

Summary:
Sulfated Sugars in Biological Processes Glycoproteins on the outside of cells are modified by the addition of sulfate moieties to their sugars. These sulfated sugars serve significant roles in cell communication. We study how sulfated sugars function in the migration of white blood cells throughout the body and in the regulation of cancer cell growth.

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.

Melvin M Scheinman, M.D.
Professor

Research Interests:
Mechanisms of cardiac arrhythmias. Cardiac electrophysiology. Catheter ablation of arrhythmogenic foci.

Summary:
My current research interests involve looking at mechanisms of supraventricular arrhythmias with respect to ablative therapy. In addition, we have initiated a cardiac genetic arrhythmic clinic Ð to help define newer genes in causation of serious ventricular arrhythmias.

We are also studying the mechanism of atypical atrial flutter in humans. We have described the occurrence of double-wave reentry (1), and have extended these observations to describe an entity known as lower-loop reentry (2) which is also isthmus dependent. We have described a new type of atypical atrial flutter involving the left membranous septum and this work was presented at the North American Society of Pacing and Electrophysiology meetings (3).

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.

Robin M. Shaw, M.D., Ph.D.
Asst Professor In Residence

Research Interests:
Cardiac Electrophysiology, Ion Channels, Arrhythmia, Sudden Cardiac Death, Heart Failure

Summary:
The basic function of the heart is to work as a pump, circulating blood through the lungs and the rest of the body. Each heartbeat, millions of individual heart cells contract in synchrony for one overall large contraction. Improper contraction results in congestive heart failure and improper synchrony results in sudden cardiac death. My laboratory studies the basic biology of heart cell contraction and synchronous communication with a goal of developing novel treatment strategies of both heart failure and sudden cardiac death.

Dean Sheppard, M.D.
Professor In Residence

Research Interests:
In vivo function of integrins and molecular basis of lung diseases

Summary:
Dean Sheppard's laboratory studies how cells respond to and modify their surroundings using receptors called integrins. They have found important roles for integrins in lung and kidney fibrosis, septic shock, acute lung injury, asthma and stroke and are testing drugs targeting integrins in animal models and in people affected by these diseases.

Kevan M Shokat, Ph.D.
Professor

Research Interests:
DESIGN OF DRUGS TO TREAT CARDIOVASCULAR DISEASE, CANCER, AND AUTOIMMUNE DISEASES.

Summary:

Paul C Simpson, M.D.
Prof In Rsdn

Research Interests:
Molecular & cellular mechanisms of myocardial hypertrophy and heart failure Adrenergic receptors, signaling, and drug development

Summary:
Dr. Simpson is working to develop new drugs to treat heart failure, one of the most common causes of hospitalization and death in the USA and Western World. He has recently identified a promising drug target, alpha-1-adrenergic receptors, and is working to translate this into clinical use.

Matthew L Springer, Ph.D.
Associate Professor In Residence

Research Interests:
Angiogenesis, VEGF, stem cells, progenitor cells, gene therapy, heart failure, myocardial infarction, coronary artery disease, cardiac regeneration, peripheral artery disease, vascular injury, nitric oxide, flavanols, skeletal muscle myoblasts, secondhand smoke

Summary:
Our research interests include cell therapy and gene therapy approaches to studying cardiovascular disease, with the goals of exploring potential treatments and understanding underlying mechanisms involved in angiogenesis, vascular function, and treatments for myocardial infarction. The laboratory is studying differential responses of cardiac and skeletal muscle to angiogenic gene therapy in mice, focusing on effects of VEGF and pleiotrophin on the vasculature. Further interests center in the therapeutic effects of bone marrow cell implantation into the heart after myocardial infarction, using an ultrasound-guided injection approach that we have developed in collaboration with the Yeghiazarians lab, with a special emphasis on the therapeutic implications of the age and cardiac disease status of the cell donor. Similarly, the lab is studying the effects of age and disease on circulating endothelial progenitor cells, with a focus on the roles of endothelial nitric oxide synthase and nitric oxide in the function of these cells. Lastly, we have developed a rat model of endothelium-dependent flow-mediated vasodilation, and are using it to examine mechanisms underlying vascular reactivity and how they are affected by cigarette smoke exposure and dietary flavanols.

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.

David F Teitel, M.D.
Prof In Res

Research Interests:
Pediatric cardiology, developmental cardiovascular physiology, cardiac mechanics, pediatric interventional cardiac catheterization, computer technology in cardiology, heart center administration, medical education, digital technology in learning, bioinformatics.

Summary:
Congenital heart disease is extremely common, occurring in about 1% of all births. My goals are to advance our knowledge of heart function in such infants and children, and to develop new methods to treat them, using medicines and catheter based techniques rather than surgery.

Mark E Von Zastrow, Ph.D., M.D.
Professor

Research Interests:
Subcellular organization and dynamics of receptor-mediated signaling systems in eukaryotic cells.

Summary:
Our laboratory studies mechanisms by which receptors that control cardiovascular biology are regulated. These receptors are important therapeutic targets and their regulation is known to be disturbed in a number of important disease states.

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.

Orion D Weiner, Ph.D.
Asst Professor In Residence

Research Interests:
Cell polarity, chemotaxis, actin cytoskeleton, cell signaling, cell migration, microscopy, biochemistry, neutrophils, systems biology, self-organization, inflammation, Rac, PI3Kinase, WAVE complex.

Summary:
Proper movement in response to cues from the outside world is as important for single cells as it is for drivers on a busy highway. If cues are misinterpreted or the movement goes awry, terrible accidents ensue, the delicate wiring of the nervous system fails, single-celled organisms can`t hunt or mate, the immune system ceases to function properly, and cancer cells spread from one part of the body to another. How do single cells, without the benefit of a brain, interpret the subtle micro-world of attractants and repellents to decide where to go? Our research focuses on dissecting the inner workings of the cellular "compass" used to guide cells on their journey. Because the core of the compass has been conserved over more than a billion years of evolution, we have been able to combine discoveries from yeast to humans to glimpse some rough outlines of the underlying machinery. However, many of the important connections are still missing. Our research focuses on identifying these key missing components and how they are wired together to process information with the hope that we can eventually make cells move when (and where) we want them to and stop them when we don`t.

Arthur Weiss, M.D., Ph.D.
Chief of Rheumatology

Research Interests:
Cell Surface Molecules and Molecular Events Involved in Lymphocyte Activation

Summary:
Dr. Weiss studies on how the functions of cells of the immune system are regulated. The immune system protects individuals from infections and malignancies. However, it is also involved in undesirable destructive responses, such as in autoimmune and allergic diseases as well as atherosclerosis and transplant rejection.

Ethan J Weiss, M.D.

Research Interests:
Coagulation, thrombosis, hemostasis, fibrinolysis, genetics, platelet, sexual dimorphism, sex hormone signaling.

Summary:
The blood clotting system is centrally important as a means to protect from blood loss. To do so, the system must be sensitive to disruptions in blood vessels. We know from naturally occurring human genetic mutations and experiments in animals that a deficiency of function or amount of clotting related proteins leads to bleeding. Yet the system must also be specific. There is an equal body of evidence that unregulated or increased propensity to form blood clots leads to deleterious clot formation such as occurs in heart attacks, strokes, and blood clots in large veins. The clotting system therefore must maintain exquisite balance between tendency toward clotting and tendency toward bleeding. Minor changes in concentration or function of a host of known and countless unknown proteins can tip the balance in either direction. Primarily, we use the mouse as a model system to define genetic regulation of blood clotting in an attempt to define genetic changes that might predispose to tipping the balance in either direction. We hope to learn more about the molecules and pathways that lead to clot formation. We hope to define novel molecules or pathways that regulate clotting or interact with known clotting pathways. We are particularly interested in how male or female sex affects clotting in animals. We know that women are 1) less likely to form clots in clotting tests and 2) are protected as compared to men in diseases associated with increased clotting like heart attacks. This tells us that women may have evolved a system with a more favorable balance between clotting and bleeding. We hope to learn how and why that may be. Ultimately, we hope to identify new risk factors for bleeding disorders as well as the clotting associated diseases such as heart attack and stroke. Furthermore, we hope that by understanding the biological mechanisms underlying such risks, we might eventually identify novel drug targets aimed at treating or preventing bleeding, stroke, heart attack or blood clots.

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.

Prescott G Woodruff, M.D., M.P.H.
Asst Professor In Residence

Research Interests:
Genomics, Asthma, Chronic Obstructive Pulmonary Disease, Stereology, Epidemiology, Clinical Trials, Medical Education

Summary:
My research relates to two common lung diseases, asthma and chronic obstructive pulmonary disease, and falls into three specific categories: 1) the identification of molecular sub-phenotypes of these diseases, 2) the elucidation of mechanisms of inflammation and remodeling in these diseases and 3) clinical trials of novel therapies.

Allison Wanting Xu, M.Sc., Ph.D.
Assistant Professor

Research Interests:
Hypothalamic regulation of energy balance, obesity and type 2 diabetes

Summary:
Our lab's major research focus is to understand the mechanisms by which energy balance is regulated. We use a combination of mouse genetics, whole body physiology and real time imaging approaches to elucidate the function of specific hypothalamic neurons and how they integrate peripheral metabolic signals under distinct physiologic conditions.

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.

CVRIHead

CVRI Scientists

Kaveh Ashrafi, Ph.D. Assistant Professor

Harold S. Bernstein, M.D., Ph.D. Professor in Residence, Pediatrics

Brian L Black, Ph.D. Professor

Paul D Blanc, M.D., MSPH Division Chief

Elias H Botvinick, M.D. Professor In Residence

Homer A Boushey, M.D. Prof & Chief

V Courtney Broaddus, M.D. Professor

Frances M Brodsky, B.A., D. Phil. Professor

James K Brown, M.D. Assoc Prof In Rsdn & Dir

Benoit G Bruneau, B.Sc., Ph.D. Associate Professor

George H Caughey, M.D. Professor In Residence

Harold A Chapman, M.D. Professor

Israel F Charo, M.D. , Ph.D. Professor In-Residence

Kanu Chatterjee, M.D. Professor

Pao-Tien Chuang, M.D. , Ph.D. Assoc Professor In Residence

Ronald I Clyman, M.D. Prof In Rsdn Ped & CVRI

Bruce R Conklin, M.D. Professor In Residence

Michael S Conte, M.D. Chief, Vascular Surgery

Shaun R Coughlin, M.D., Ph.D. Professor

Rik M Derynck, Ph.D. Professor

Leland G Dobbs, M.D. Adjunct Professor

Mark D Eisner, A.B., M.D. , M.P.H. Assoc Professor In Residence

Joanne N Engel, M.D., Ph.D. Prof In Residence

David J Erle, M.D. Professor of Medicine In Resid

John Vincent Fahy, M.D. Professor In Residence

Robert V Farese, M.D. Professor In Residence

Christopher J Fielding, Ph.D. Professor

Jeffrey R Fineman, M.D. Professor in Residence

David G Gardner, M.D. Professor in Residence

Zev Jordan Gartner, M.S. , Ph.D. Acting Assistant Professor

Stanton A Glantz, Ph.D. Professor of Medicine

Warren M Gold, B.A., M.D. Professor

Michael Gropper, M.D., Ph.D. Professor In Residence

William Grossman, M.D. Division Chief

Samuel Hawgood, M.B., B.S., M.D. Chair

Arthur C Hill, M.D. Prof of Clinical Surgery

Julien I Hoffman, M.D., F.R.C.P. Professor Emeritus

Holly A Ingraham, Ph.D. Professor

Lily Y Jan, B.Sc., M.Sc., Ph.D. Professor

David J Julius, S.B., Ph.D. Chair and Professor

Yuet W Kan, M.D. , D.Sc. Professor

John P Kane, M.S., M.D., Ph.D. Prof

Joel S Karliner, A.B., M.D. Prof of Medicine Emeritus

Thomas B Kornberg, B.A., Ph.D. Professor & Vice Chair

Theodore W Kurtz, M.D. Prof in Res & Vice Chair

Pui-Yan Kwok, M.D., Ph.D. Professor In Residence

Stephen C Lazarus, M.D. Professor of Clinical Medicine

Randall J Lee, M.D., Ph.D. Prof of Clin Med

Wendell A Lim, Ph.D. Professor

Robert W Mahley, B.S., Ph.D., M.D. Director

Mary J. Malloy, M.D. Senate Emeritus

Michael J Mann, M.D.

Gail R Martin, Ph.D. Professor

Michael A Matthay, M.D. Professor In Residence

Donald M Mcdonald, M.D., Ph.D. Professor

Takashi Mikawa, M.S., Ph.D. Professor In Residence

Daniel L Minor, Ph.D. Associate Professor

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

Jay A Nadel, M.D. Professor

Jeffrey E Olgin, M.D. Professor In Residence

David Pearce, B.A., M.D. Professor of Medicine

Jean-Francois Pittet, M.D. Professor In Residence

Rita F Redberg, M.D., M.Sc. Professor

Jeremy F. Reiter, M.D., Ph.D. Asst Professor in Residence

Steven D Rosen, Ph.D. Professor

David H Rowitch, M.D., Ph.D. Professor

Melvin M Scheinman, M.D. Professor

Nelson B Schiller, M.D. Professor of Cardiology

Robin M. Shaw, M.D., Ph.D. Asst Professor In Residence

Dean Sheppard, M.D. Professor In Residence

Kevan M Shokat, Ph.D. Professor

Paul C Simpson, M.D. Prof In Rsdn

Matthew L Springer, Ph.D. Associate Professor In Residence

Deepak Srivastava, M.D. Director and Professor

Didier Y. R. Stainier, Ph.D. Professor

David F Teitel, M.D. Prof In Res

Mark E Von Zastrow, Ph.D., M.D. Professor

Rong Wang, Ph.D. Associate Professor in Res

Orion D Weiner, Ph.D. Asst Professor In Residence

Kaveh Ashrafi, Ph.D.
Assistant Professor

Harold S. Bernstein, M.D., Ph.D.
Professor in Residence, Pediatrics

Brian L Black, Ph.D.
Professor

Paul D Blanc, M.D., MSPH
Division Chief

Elias H Botvinick, M.D.
Professor In Residence

Homer A Boushey, M.D.
Prof & Chief

V Courtney Broaddus, M.D.
Professor

Frances M Brodsky, B.A., D. Phil.
Professor

James K Brown, M.D.
Assoc Prof In Rsdn & Dir

Benoit G Bruneau, B.Sc., Ph.D.
Associate Professor

George H Caughey, M.D.
Professor In Residence

Harold A Chapman, M.D.
Professor

Israel F Charo, M.D. , Ph.D.
Professor In-Residence

Kanu Chatterjee, M.D.
Professor

Pao-Tien Chuang, M.D. , Ph.D.
Assoc Professor In Residence

Ronald I Clyman, M.D.
Prof In Rsdn Ped & CVRI

Bruce R Conklin, M.D.
Professor In Residence

Michael S Conte, M.D.
Chief, Vascular Surgery

Shaun R Coughlin, M.D., Ph.D.
Professor

Rik M Derynck, Ph.D.
Professor

Leland G Dobbs, M.D.
Adjunct Professor

Mark D Eisner, A.B., M.D. , M.P.H.
Assoc Professor In Residence

Joanne N Engel, M.D., Ph.D.
Prof In Residence

David J Erle, M.D.
Professor of Medicine In Resid

John Vincent Fahy, M.D.
Professor In Residence

Robert V Farese, M.D.
Professor In Residence

Christopher J Fielding, Ph.D.
Professor

Jeffrey R Fineman, M.D.
Professor in Residence

David G Gardner, M.D.
Professor in Residence

Zev Jordan Gartner, M.S. , Ph.D.
Acting Assistant Professor

Stanton A Glantz, Ph.D.
Professor of Medicine

Warren M Gold, B.A., M.D.
Professor

Michael Gropper, M.D., Ph.D.
Professor In Residence

William Grossman, M.D.
Division Chief

Samuel Hawgood, M.B., B.S., M.D.
Chair

Arthur C Hill, M.D.
Prof of Clinical Surgery

Julien I Hoffman, M.D., F.R.C.P.
Professor Emeritus

Holly A Ingraham, Ph.D.
Professor

Lily Y Jan, B.Sc., M.Sc., Ph.D.
Professor

David J Julius, S.B., Ph.D.
Chair and Professor

Yuet W Kan, M.D. , D.Sc.
Professor

John P Kane, M.S., M.D., Ph.D.
Prof

Joel S Karliner, A.B., M.D.
Prof of Medicine Emeritus

Thomas B Kornberg, B.A., Ph.D.
Professor & Vice Chair

Theodore W Kurtz, M.D.
Prof in Res & Vice Chair

Pui-Yan Kwok, M.D., Ph.D.
Professor In Residence

Stephen C Lazarus, M.D.
Professor of Clinical Medicine

Randall J Lee, M.D., Ph.D.
Prof of Clin Med

Wendell A Lim, Ph.D.
Professor

Robert W Mahley, B.S., Ph.D., M.D.
Director

Mary J. Malloy, M.D.
Senate Emeritus

Gail R Martin, Ph.D.
Professor

Michael A Matthay, M.D.
Professor In Residence

Donald M Mcdonald, M.D., Ph.D.
Professor

Takashi Mikawa, M.S., Ph.D.
Professor In Residence

Daniel L Minor, Ph.D.
Associate Professor

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

Jay A Nadel, M.D.
Professor

Jeffrey E Olgin, M.D.
Professor In Residence

David Pearce, B.A., M.D.
Professor of Medicine

Jean-Francois Pittet, M.D.
Professor In Residence

Rita F Redberg, M.D., M.Sc.
Professor

Jeremy F. Reiter, M.D., Ph.D.
Asst Professor in Residence

Steven D Rosen, Ph.D.
Professor

David H Rowitch, M.D., Ph.D.
Professor

Melvin M Scheinman, M.D.
Professor

Nelson B Schiller, M.D.
Professor of Cardiology

Robin M. Shaw, M.D., Ph.D.
Asst Professor In Residence

Dean Sheppard, M.D.
Professor In Residence

Kevan M Shokat, Ph.D.
Professor

Paul C Simpson, M.D.
Prof In Rsdn

Matthew L Springer, Ph.D.
Associate Professor In Residence

Deepak Srivastava, M.D.
Director and Professor

Didier Y. R. Stainier, Ph.D.
Professor

David F Teitel, M.D.
Prof In Res

Mark E Von Zastrow, Ph.D., M.D.
Professor

Rong Wang, Ph.D.
Associate Professor in Res

Orion D Weiner, Ph.D.
Asst Professor In Residence

Arthur Weiss, M.D., Ph.D.
Chief of Rheumatology

Zena Werb, Ph.D.
Professor and Vice Chair