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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

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

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

Jay A Nadel, M.D. Professor Research Interests: Signaling mechanisms in airway epithelium Summary: Lungs defend the host against inhaled Òinvaders' 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.

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:

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.

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.

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.