Fielding, Christopher J

Stainier, Didier Y. R.

Wiener-Kronish, Jeanine

Young, William L

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. Obesity is a global epidemic common to all socio-economic and age groups. 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 body fat and the progression of obesity related disorders. Fat regulation is under tight control of a complex network of checks and balances between the feeding regulatory centers in the brain and fat storage and energy utilizing sites in the body. How genetic and environmental factor interact to impact body 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 microscopic worm has been used extensively to study animal development, aging, and pathways implicated in human diseases. This is because it many of its 20,000 genes have significant similarity to human genes. Using genetic and genomic techniques, we have identified over 400 genes that, when inactivated, impact fat regulation in these animals. These include genes whose mammalian counterparts were previously shown to be important in fat regulation as well as many genes previously unassociated with fat content. The shared ancestry of known mammalian and C. elegans fat regulatory genes suggests that many of the newly identified genes similarly impact fat regulation in mammals. Our efforts are now aimed at elucidating the modes of function and regulation of the newly identified genes. We have already shown that some of these genes function in the C. elegans nervous system to centrally regulate fat and feeding pathways while other genes function at the sites of fat storage to regulate metabolism. Based on our findings we have initiated collaborative studies to identify mammalian obesity genes.

Diane L. Barber, Ph.D.
Professor of Cell & Tissue Biology

Research Interests:
Signal transduction and Ion xchangers

Summary:
The research in Diane Barber's laboratory focuses on the regulation and function of two families of plasma membrane ion exchangers, the Na-H exchangers and the Cl-HCO3 exchangers, which regulate intracellular pH. Studies on the regulation of these ion exchangers are designed to investigate the intracellular signaling pathways mediating their activation by hormone and growth factor receptors. Studies on their function are designed to investigate how their regulation of intracellular pH and the actin cytoskeleton contribute to cell growth, differentiation, and migration.

One current emphasis is to map GTPase- and kinase-dependent signaling pathways mediating receptor regulation of plasma membrane ion exchangers. To accomplish this we are using two genetic approaches. The first is to express genetically altered alleles in cells to determine the effects on a particular signaling pathway or cellular response. Using this approach, we determined that the Rho family of GTPases plays a predominant role in mediating activation of ion exchangers by hormone and integrin receptors. We also identified specific Rho-regulated kinases that directly phosphorylate and regulate plasma membrane ion exchangers. The second approach we use relies on interaction cloning strategies to identify protein-protein interactions as a means of determining direct regulators and effectors of ion exchangers. These cloning strategies were used to identify novel kinases and calcium-binding proteins that directly associate with plasma membrane ion exchangers.

A second current emphasis is to characterize the role of Na-H exchangers in GTPase-dependent cell functions such as proliferation, neoplastic transformation, and migration. We determined that Na-H exchangers regulate these cell functions not only through their well-characterized action on intracellular pH homeostasis, but also through a newly identified action on regulating the organization of the actin cytoskeleton. We found that Na-H exchangers play a critical role in mediating cytoskeletal reorganization by integrin receptors and by the Rho family of GTPases, and that they are structurally linked to the actin-based cytoskeleton through a direct association with actin-binding proteins of the protein 4.1 superfamily. Hence, we have identified a novel function of Na-H exchangers in linking the actin cytoskeleton to the plasma membrane. How this novel function contributes to cytoskeletal organization during integrin- and GTPase-dependent cell contractility and migration is currently being determined.

The work in our laboratory is specifically relevant to the CVRI program. We are studying the molecular mechanisms controlling basic cellular processes contributing to cell growth, contractility, and migration. The Na-H exchanger is an important mediator for the inotropic effects of a1-adrenergic agonists, endothelins, and angiotensin II, and its activation is a major mechanism for restoring intracellular pH after acidosis. Influx of extracellular Na+ via this exchanger is a key factor in myocardial pathology associated with ischemia and reperfusion. Additionally, upstream activators of the Na-H exchanger, such as integrins and the GTPase Ga13, regulate the development of the cardiovascular system. Our recent work demonstrating that the Na-H exchanger is critical for cytoskeletal remodeling in response to integrins and Ga13 suggests that its actions on the cytoskeleton may be important for the development and maintenance of cardiovascular functions.

Harold S. Bernstein, M.D., Ph.D.
Associate Professor of 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.
Associate Professor of Biochemistry & Biophysics

Research Interests:
Cardiac and skeletal muscle development, differentiation, and function

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

Paul D. Blanc, M.D.
Professor Medicine; Division Chief, Occupational Medicine

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

Summary:
Dr. Blanc's research program focuses on the epidemiology and toxicology of the pulmonary system. The research is comprised of two principal components: first, the longitudinal study of adults with asthma, examining outcomes of disease with emphasis on interactions between workplace exposures and disease severity and second, epidemiologic, population-based and controlled human exposure studies of acute chemical exposure effects. The research has been supported by a Research Career Development Award from the National heart Lung and Blood Institute and independent research grants from the NIH, CDC, American Lung Association, and the UC Tobacco-Related Diseases research Program.

Homer A. Boushey , M.D.
Professor of Medicine; Division Chief, Allergy & Immunology

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

Summary:
Dr. Boushey received his M.D. degree from the UCSF in 1968. He completed residency training in Internal Medicine at UCSF and at the Beth-Israel Hospital of Harvard Medical School. He then pursued specialty training in Pulmonary Medicine at Oxford University and at UCSF. He joined the UCSF faculty in 1974 and, except for a year's sabbatical at the University of Paris (Cochin Hospital), has remained here for his entire career. He has served as Vice-Chair of the Department of Medicine and Chief of the Medical Service (1989-1995) and recently as Chief of the Division of Allergy/Immunology and Director of the Asthma Clinical Research Center. Dr. Boushey's major academic interests include clinical research on the pathogenesis and treatment of asthma, focusing especially on the role of viral respiratory infections in triggering asthma exacerbations.

Asthma has come to be regarded as a chronic inflammatory disease of the airways, but the causes, nature, and consequences of inflammation are imprecisely understood. Working closely with Drs. Fahy (Pulmonary), Avila (Allergy), Lazarus (Pulmonary), and Janson (Pulmonary, School of Nursing), Dr. Boushey's research team has focused on methods for assessing airway mucosal inflammation (eg., sputum induction), on examining the effects of new, specifically targeted therapies (egs., monoclonal anti-IgE antibody, cell adhesion molecular inhibitors), on comparing existing therapies (inhaled corticosteroids, long-acting beta-agonists, and leukotriene antagonists, given alone or in combination), and on defining the mechanisms by which viral respiratory infection alters upper and lower airway function.

Asthma occurs uniquely in humans, and while animal models offer great promise for defining key steps in the pathophysiologic cascade that accounts for the structural and functional changes in asthma, confirmation of the relevance and importance of new findings ultimately requires testing in humans with the disease. Conversely, new targets for study through the application of genetic manipulation in murine models sometimes are defined by observations made in human subjects. The exchange of information between bench and clinical investigators is facilitated by the development and application of tests based on advances in molecular biology and genetics to the study of people. The era of truly "translational" research is opening, and will open first to centers where basic and clinical investigation is closely integrated, and where basic and clinical investigators have a tradition of exchange. Dr. Boushey regards these traditions at UCSF as essential for his own success in clinical research, and believes they also serve for the training of future academic investigators.

V. Courtney Broaddus, M.D.
Professor of Medicine

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:
Apoptosis is a highly regulated process of cell death, allowing the deletion of cells that are damaged or otherwise targeted for destruction. Resistance to apoptosis underlies both the development and the survival of tumors. Understanding the sites of resistance in tumors may lead to more effective therapy. Two signaling pathways are known to activate the proteases called caspases that mediate apoptosis: one, the DNA damage pathway which involves a mitochondrial step in order to activate caspases and the other the death ligand pathway which can bypass mitochondria to activate caspases directly. Crosstalk between the pathways may lead to synergistic apoptotic responses.

We study apoptosis in mesothelioma and lung cancer lines, as models for highly resistant solid tumors. A major focus of the laboratory is 1) to identify mechanisms of resistance to apoptosis in these lines and 2) to identify means of amplifying apoptosis. We have now described a synergistic apoptotic response of mesothelioma lines when exposed to both a death ligand, TNF-related apoptosis inducing ligand (TRAIL), and chemotherapeutic agents. The synergy can be shown to involve amplification of mitochondrial depolarization and amplified release of cytochrome c. We are now studying the signaling steps by which these two pathways (death receptor and DNA damage) converge on the mitochondria andamplify apoptotic death. Other synergistic combinations appear to act at different levels within the cell, e.g. by increasing expression of the death receptors. Some examples of interest are the use of TRAIL or fas ligand together with proteasome inhibitors, with NFkappa B inhibition, and with triptolide, an inhibitor of cell arrest. In parallel in vivo studies, we are exploring synergistic effects in a nude mouse model of mesothelioma.

In other work, we are starting microarray analysis of the response of mesothelial cells to toxic entities, such as asbestos fibers. In this approach, now called toxicogenomics, microarray studies of global cell responses to toxic agents may identify patterns of responses associated with toxicity. The analysis can highlight previously unrecognized toxic interactions with cells, allowing new hypotheses to be developed and explored.

James K. Brown, M.D.
Associate Professor of Medicine

Research Interests:
Protease signaling

Summary:
Tryptase is the most abundant protein released from mast cells, which are inflammatory cells found in large numbers in the airways and lungs of patients with respiratory diseases such as asthma and pulmonary fibrosis. When released from mast cells, tryptase has the capacity to stimulate growth in nearby cells. Therefore, it may contribute to thickening of the airway wall in asthma, leading to increased airflow obstruction, and to scar formation in the lungs in pulmonary fibrosis, leading to worsening shortness of breath. Our research seeks to understand the mechanisms through which tryptase stimulates cells to grow so that improved pharmaceutical approaches can be developed to inhibit its growth stimulatory effects and can be employed as possible therapeutic agents in patients with asthma and pulmonary fibrotic disorders.

Benoit G Bruneau,
Associate Professor

Research Interests:
Heart development, congenital heart disease, chromatin, embryogenesis, transcription

Summary:
Our lab studies how genes are turned on in the heart, and the proteins that control these genetic switches. These proteins are called transcription factors, and many of them have been found to be mutated in human congenital heart disease. So these studies have helped understand how congenital heart defects happen. We are also interested in how transcription factors turn on heart genes, and from these studies we have identified new proteins, called chromatin remodeling factors, that help turn on heart genes. Using this knowledge, we are beginning to understand how to make new heart cells, which could in the future be useful for cardiac regeneration.

George H. Caughey, M.D.
Professor of Medicine; Chief, Pulmonary & Critical Care Medicine Section, VAMC

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

Summary:
The laboratory's main goal is to understand the roles of enzymes released into the lungs and breathing tubes by mast cells and related white blood cells. Our studies suggest that these enzymes-specifically, tryptases and chymases, which alter the properties of selected target proteins by disrupting links in chains of amino acids-may be important in asthma, bronchitis, lung infections and diseases characterized by lung shrinkage and excessive scarring. The laboratory is also interested in a related enzyme, prostasin, which may regulate airway water content in cystic fibrosis, and in several enzymes that may promote airway scarring and recurrence of breathing problems in recipients of transplanted lungs.

Harold A. Chapman, M.D.
Professor of Medicine; Chief, Division of Pulmonary and Critical Care Medicine

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:
Integrins are a well known family of cell surface adhesion protein receptors. Integrins attach to the matrix surrounding cells, and also to neighboring cells, and then convey information to the cell allowing it to respond. For example, cells suddenly devoid of their integrin attachments to their surrounding matrix frequently undergo a cell death program. Integrin function therefore affects cellular differentiation state, survival, growth, and movement. My lab has been studying a set of integrins widely expressed on epithelial cells and attempting to understand how the information conveyed by these integrins is regulated and whether there are critical pathways of signaling initiated through integrins that are needed for tumor progression and wound healing. The lab is primarily focused on the lung and hence our experimental models are mainly intended to model pulmonary fibrosis (scarring) and lung cancer.

The main objectives of our current studies related to integrins are to understand integrin function in the context of epithelial cell trans-differentiation to fibroblast-like cells during lung repair (wound healing) and in the context transformed epithelial cell (carcinoma) metastasis to and within the lung. We believe both of these processes may be critically dependent on integrins..

More detailed descriptions of current projects related to integrins as well as to the cathepsin (endosomal protease) part of the lab, current lab members, and recent publications, are provided within the lab website link (pulmonary.ucsf.edu/chapmanlab).

Israel F. Charo, M.D. , Ph.D.
Senior Investigator, Gladstone Institute of Cardiovascular Disease

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.
Ernest Gallo Distinguished Professor of Medicine

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.
Associate Professor of Biochemistry & Biophysics

Research Interests:
Cell-cell signaling during mammalian development and in postnatal physiology

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

Ronald I. Clyman, M.D.
Professor of Pediatrics

Research Interests:
Cardiology, cell biology, developmental biology, neonatology, neonatal cardiology

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

Bruce R. Conklin, M.D.
Associate Investigator, Gladstone Institute of Cardiovascular Disease

Research Interests:
Rewiring G protein signals in vivo

Summary:
Hormone receptors help to coordinate the development and function of tissues such as the heart. The largest known family of receptors for hormones and drugs are the G proteinÐcoupled receptors, with over 700 human genes. Many of the mostly widely used drugs work on these receptors, so it is of great medical interest to find out how they work. We focus on how these receptors work in embryonic stem (ES) cells, since these cells can develop into beating heart cells in a few days. This way we can rapidly turn on or off receptor signaling pathways, and see what happens in the ES-derived heart cells. Most of our work is with mouse ES cells, but we also work with human ES cells when technically possible.

Since many of our experiments produce overwhelming amounts of data we write computer software programs to help analyze these data in the context of known biological pathways. One of our programs is freely distributed (www.GenMAPP.org) and has over 13,000 registered users. For many biologists GenMAPP has become like an 'Adobe Acrobat' for biological pathways, since they can exchange pathway information without buying expensive software. We continue to develop free open-source software to accelerate our own research while helping the community of biologists. In the future, we are particularly interested in designing software to study human genetic variations that could be associated with disease. By combining pathway-oriented bioinformatics with high-throughput experimental methods that probe these pathways, we are gaining insights into the molecular basis for hormonal control of heart development and function.

Shaun R. Coughlin, M.D., Ph.D.
Professor of Medicine and Cellular & Molecular Pharmacology; Distinguished Professorship in Cardiovascular Biology & Medicine; CVRI Director

Research Interests:
Signaling mechanisms in cardiovascular biology and disease, thrombin signaling

Summary:
How are the thrombi that cause most heart attacks and strokes formed? How is normal blood clotting at a site of tissue injury triggered? Tissue injury initiates the formation of a protease called thrombin at the injury site, and thrombin is the central mediator of blood clotting. Proteases are best known for their ability to cleave or digest other proteins, but some can act like a hormone to trigger specific cellular responses. Indeed, thrombin causes platelets, small specialized blood cells, to aggregate at sites of injury to plug bleeding blood vessels. It is this same process that blocks diseased blood vessels in the heart or brain to cause heart attacks and some strokes. How does a protease like thrombin behave like a hormone to regulate the behavior of platelets and other cells? We've characterized a family of protease-activated receptors (PARs) that provide an answer. PAR1 is the key mediator of thrombin's effect on human platelets. Part of PAR1 is displayed on the outside of the platelet, poised to sense its environment. Thrombin binds to and cleaves this part of PAR1, and this cleavage event triggers a change in the shape of the receptor that sends information across the cell membrane to switch on signaling molecules inside the platelet. PAR1 is the prototype for a family of four related receptors that appear to account for most cellular responses to thrombin and related proteases. Our laboratory currently focuses on understanding the roles of protease and PAR signaling and, more broadly, G protein-coupled receptors in cardiovascular biology.

One important line of research uses mice made to lack one or more PARs. Such studies showed that PARs are necessary for platelets to respond to thrombin and for enlargement and propagation of platelet thrombi at sites of blood vessel injury. Interestingly, PAR signaling is unnecessary for formation of initial small juxtamural platelet thrombi, the kind of thrombin that are capable of plugging a small hole in the wall of a small blood vessel but not capable of blocking a major artery. Thus different signaling mechanisms appear to be important at different points in the development of a thrombus and exploiting such differences may permit the development of safer antithrombotic drugs. Specifically, PAR1 blockers may be useful in this regard. Mouse studies have also revealed that proteases and PARs play unexpected roles in the formation of the cardiovascular system and the nervous system in the embryo, roles which we are working to characterize. Lastly, PARs are members of a much larger family of receptors known as G protein-coupled receptors. These receptors regulate a host of physiological processes and it is clear important roles remain to be uncovered. The ~350 G protein-coupled receptors in mice and humans couple through four main G protein families, Gs, Gq, Gi, and G12/13. We are ablating G12/13 and Gi signaling in specific cell types in mice to probe the roles of these pathways in cardiovascular development, metabolism, blood and bone formation, and other important processes, then using a candidate approach to identify the receptors and ligands involved. We expect these studies will point up new strategies for treating diseases of the systems under study.

Rik M. Derynck, Ph.D.
Professor of Cell & Tissue Biology

Research Interests:
Transmembrane TGF-a and TGF-b receptor signaling in cell proliferation and differentiation.

Summary:
Our research focuses on the role of TGF-a and b, two structurally related growth and differentiation factors, in epithelial and mesenchymal cell proliferation and differentiation. We use various cell biological, molecular and biochemical approaches to address cell physiological and developmental questions.

TGF-a is a growth factor for various cell types from ectodermal origin, including most epithelial cells, and exerts its functions in an autocrine and paracrine fashion. TGF-a is normally made as a transmembrane protein at the cell surface and functions in cell communication through its ability to interact with a tyrosine kinase receptor. The ectodomain can be proteolytically released in a highly regulated manner and is then released. Our TGF-a research focuses on the identification and functional characterization of proteins that form a complex in association with transmembrane TGF-a. We study their functions in the presentation of transmembrane TGF-a, signaling and regulation of TGF-aectodomain cleavage in normal and transformed epithelial cells. We are also characterizing the signaling mechanisms that lead to ectodomain cleavage of transmembrane TGF-a and consequent release of soluble TGF-a.

TGF-b is a prototype for a large family of growth and differentiation factors which regulate development. TGF-b is also a potent inducer of growth arrest in many cell types. Our research focus is on the mechanism of signaling by TGF-b receptors and its role in mesenchymal differentiation. We study how the Smads, a novel class of intracellular signaling effectors, act as signal transducers following receptor activation, are translocated into the nucleus and regulate gene expression. We also study how this signaling regulates mesenchymal cell differentiation into muscle, bone and fat cells. Finally, we also focus on the characterization of novel signaling pathways, separate from the Smads, that are activated by TGF-b receptors.

Leland G. Dobbs, M.D.
Adjunct Professor of Medicine and Pediatrics

Research Interests:
Pulmonary alveolar epithelial development and response to injury, development of biomarkers for the measurement of lung injury

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

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

Research Interests:
Title: 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.
Associate Professor of Medicine and Microbiology & Immunology

Research Interests:
Bacterial Pathogen-Host Cell Interactions

Summary:
Infectious diseases are the third leading cause of death in the US and the leading cause worldwide. 95% of all infectious agents enter through mucosal surfaces, such as the linings of the gastrointestinal, respiratory, and genito-urinary tracts. My lab studies the interactions of two bacteria that are important causes of human disease with the mucosal surface. Using a combination of genetics and cell biology, we are studying how Pseudomonas aeruginosa injures host cells and how Chlamydia trachomatis infects human cells. By unraveling the basic mechanisms by which these pathogens cause disease, we may be able to design new drugs, vaccines, or diagnostic strategies. Our studies also reveal new insights into fundamental biologic processes of broad significance.

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

Research Interests:
Asthma, allergy and inflammation; functional genomics

Summary:
We are studying how substances produced by the immune system contribute to allergic reactions in the lungs and to asthma, a disease which affects more than 10 million Americans annually. The role of T cell cytokines in murine models of asthma: T helper cells are increased in airways of people with asthma. In animal models, cytokines produced by these cells cause airway inflammation, mucus overproduction, and airway hyperresponsiveness (all of which are hallmarks of asthma). We are working with a variety of mouse models of asthma in order to understand the mechanisms of these cytokine effects. For example, we have produced transgenic mice that lack the capacity to respond to specific cytokines in all cells except airway epithelial cells. These experiments, together with experiments involving cultured human lung cells, allow us to directly determine how the effects of these cytokines on epithelial cells contribute to asthma pathogenesis.

Functional genomics: The sequencing of the human genome marks the beginning of a new era in biological research. We are producing tools that allow for the large-scale analysis of gene expression in human and mouse cells and tissues. The current focus is on the production and use of oligonucleotide microarrays. We are working closely with collaborators at UCSF and elsewhere, and are using microarrays to address problems relevant to asthma and other lung diseases.

John Vincent Fahy, M.D.
Professor of Medicine

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, Jr., M.D.
Senior Scientist, J. David Gladstone Institutes, Professor of Medicine and of Biochemistry & Biophysics

Research Interests:
Cell Biology of Energy Metabolism

Summary:
"The ability of cells to store and utilize energy in a regulated manner is fundamental to life, and abnormalities in energy metabolism play a central role in diseases such as obesity, type two diabetes, neurodegeneration, and aging. Our laboratory is interested in cellular energy homeostasis, focusing on three interrelated areas of research: the cell biology of lipid storage, the enzymes of neutral lipid synthesis, and energy metabolism in neurons. Our approaches are basic, emphasizing biochemistry and cellular biology, with specific hypothesis testing in model organisms such as flies and mice. Our group has two new areas of investigation: 1) the cell biology of lipid droplet formation and utilization, and 2) neuron cell biology and neurodegeneration, with a focus on frontotemporal dementia. For more information on our laboratory, please visit our laboratory web site (www.gladstone.ucsf.edu/gladstone/files/farese/HomePage/index.html)."

Christopher J. Fielding, Ph.D.
Professor of Physiology

Research Interests:
Structure-function analysis of cholesterol-binding proteins

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.

Phoebe Fielding, Ph.D.
Adjunct Professor of Medicine

Research Interests:
Caveolin and caveolae: Roles in cholesterol transport and signaling

Jeffrey R Fineman, M.D.
Professor of Pediatrics

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:
Tobacco is the leading preventable cause of heart disease and heart disease is the leading cause of death due to smoking. We conduct research on a wide range of issues, ranging from the effects of secondhand smoke on the heart through the reductions in heart attacks observed when smokefree policies are enacted, to how the tobacco industry fights against tobacco control programs. In particular, we study the effectiveness of different tobacco control strategies, particularly in the context of large state-run tobacco control programs and international tobacco control issues, with emphasis on how the tobacco industry is working to prevent implementation of meaningful tobacco control policies. We have also identified the importance of young adults (not just teens) as targets for the tobacco industry and efforts at smoking cessation and tobacco use prevention. Our research on the effects of secondhand smoke on blood and blood vessels has helped explain why, in terms of heart disease, the effects of secondhand smoke are nearly as large as smoking. Consistent with what would be expected from the biology of secondhand smoke, we demonstrated a large and rapid reduction in the number of people admitted to the hospital with heart attacks in Helena, Montana, after that community made all workplaces and public places smokefree. Our work in this area was identified as one of the top research advances for 2005 by the American Heart Association.

William Grossman, M.D.
Professor of Medicine; Chief, Division of Cardiology

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.
Professor and Chair of Pediatrics

Research Interests:
Structure and function of surfactant apoproteins

Summary:
Our research activity is focused on the biology of the pulmonary alveolus with a particular emphasis on the structure and function of the pulmonary surfactant apoproteins. The human lung is made up of some 500 million alveoli each with a diameter of 200 microns and a septal wall thickness of only 5-8 microns. The large surface area provided by this foam-like architecture is ideal for rapid respiratory gas exchange but necessitates some unique biological answers to the threat to structural stability posed by the problem of high surface tension and the constant exposure to environmental pollutants, allergens and microbes. Pulmonary surfactant, a lipoprotein secretion of the alveolar epithelial type II cell, stabilizes alveolar structure at low transpulmonary pressures by reducing the retractile surface forces that would otherwise act to collapse the lung at end expiration. The surfactant apoproteins also act as components of the pulmonary innate defense system protecting the lung from inflammation and infection.

A derangement of alveolar stability, secondary to a developmental deficiency of surfactant, is the major factor in the pathogenesis of the respiratory distress syndrome of the newborn (RDS). My interest in the biology of surfactant grew from clinical experience in neonatology where RDS is a major cause of neonatal death. I moved to UCSF in 1982 as a research fellow with Dr. John Clements, the scientist who discovered surfactant in the late 1950's. He started his own laboratory, focused on the proteins associated with surfactant, in 1984. By 1985 our laboratory had identified three novel surfactant-associated proteins, now known as SP-A, SP-B and SP-C, and had derived their primary structures from full-length cDNA and genomic clones. In 1993, Erica Crouch in St. Louis described a fourth protein, SP-D. The higher-order structure, genetic regulation, metabolism, and function of these proteins have been the focus of our research since that time.

We now know that the surfactant proteins have important roles in the activity of surfactant, particularly the ability to rapidly spread phospholipids at the alveolar surface. The proteins also regulate surfactant turnover and metabolism in the alveolus and play a part in non-antibody mediated response to infection and inflammation in the alveolus. The biology of these proteins is complex and they apparently function as interacting hetero-oligomers to mediate their multiple effects on surfactant biology. At least two of the surfactant proteins, SP-B and SP-C, are present in exogenous surfactants approved for clinical use and fatal human disease has been linked to inherited mutations in both these proteins. This clear link to human disease provides a strong rationale to obtain a detailed understanding of their structure and function.

Holly A. Ingraham, Ph.D.
Professor of Physiology

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, Ph.D.
Professor of Physiology and Biochemistry & Biophysics; Investigator, Howard Hughes Medical Institute; Jack and DeLoris Lange Endowed Chair of Physiology and Biophysics

Research Interests:
Studies of potassium channels

Summary:
Potassium channels are widely distributed. In the brain, potassium channels regulate neuronal signaling. Potassium channels may also regulate cell volume and the flow of salt across epithelia, control heart rate, vascular tone, the release of hormones such as insulin, and protect neurons and muscles under metabolic stress.

How can potassium channels serve so many different physiological functions? Potassium channels come in many different flavors; they differ in how their activities are regulated as well as the exact manner they allow passage of potassium ions. Many different potassium channels often co-exist in a cell. This richness in potassium channel variety was one of the factors that stemmed early attempts for biochemical purification of potassium channels.

How does a potassium channel allow potassium ions but not the smaller sodium ions to go through? How does a potassium channel alter its activity in response to electrical and chemical signals? How do potassium channels contribute to signaling and plasticity in the brain? How does a cell control the number and type of potassium channels in its subcellular compartments? How might potassium channels have arisen during evolution? We have been fascinated with these questions, and believe what potassium channels will teach us may also be of relevance to other membrane proteins.

To study potassium channels, we have chosen a molecular approach that isolates individual potassium channel genes so that the channels they give rise to can be studied one at a time and then compared with potassium channels in native tissues. This molecular study was initiated by positional cloning of the Shaker voltage-gated potassium (Kv) channel gene in the fruit fly and expression cloning of mammalian inwardly rectifying potassium (Kir) channels, founding members of two large, distantly related families of potassium channels in organisms ranging from bacteria to man.

Potassium channel mutations cause diseases of the brain (epilepsy, episodic ataxia), ear (deafness), heart (arrhythmia), muscle (myokymia, periodic paralysis), kidney (hypertension), pancreas (hyperinsulinemic hypoglycemia, neonatal diabetes), and developmental abnormalities of neural crest-derived tissues (Andersen's syndrome). Conversely, the KCNK9 potassium channel gene acts as a dominant oncogene and is amplified or otherwise over-expressed in several types of human carcinomas. Underscoring potassium channels' critical physiological functions, potassium channel openers and blockers have been developed for pharmaceutical purposes. A better understanding of potassium channel function will not only satisfy our curiosity, but will have clinical significance.

How do we study potassium channels? One unique advantage in channel studies is the possibility to examine one channel at a time, with sub-millisecond resolution, for many seconds, in experimentally determined intracellular and extracellular environments. In addition to biophysical, biochemical, and cell biological studies of channel assembly, trafficking, regulation and function, we need to learn how potassium channels are targeted to specific subcellular compartments of neurons in the mammalian brain, how they respond dynamically to neuronal activity and in turn modulate neuronal signaling. To understand how potassium channels work, it will be necessary to explore advances in genomics as well as genetics, and incorporate any useful methodologies suited for membrane proteins.

Yuet W. Kan, M.D.
Professor of Medicine and Laboratory Medicine; Louis K. Diamond Professor of Hematology

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:
Our laboratory is investigating the diagnosis and treatment of diseases using recombinant DNA technology. Research is being carried out on the diagnosis of genetic diseases by testing fetal cells in the maternal circulation, thus avoiding any possible risk to the unborn child. Treatment of important genetic diseases such as sickle cell anemia and thalassemia using embryonic stem cells is being investigated, as is the treatment of coronary heart disease using gene and cell therapy.

John P. Kane, M.S., M.D., Ph.D.
Professor of Medicine and Biochemistry & Biophysics

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

Summary:
Because it has been found that faulty transport of cholesterol and other lipids is an underlying element in the development of arteriosclerosis, elucidation of molecular mechanisms involved in cholesterol transport has been a major goal of this group. This has led to the identification of previously unidentified proteins that participate in the process. Certain complexes of cholesterol and other fatty substances with proteins (lipoproteins) are known to convey cholesterol to the artery wall to initiate the formation of diseased areas (plaques) that can eventually lead to occlusion of arteries serving the heart or brain. Others (High Density Lipoproteins, HDL) have the task of removing cholesterol to protect the arteries. Understanding how HDL accomplish this task requires the discovery and characterization of previously unknown molecular complexes. Whereas it was thought that there were two species of HDL, work by this group has identified sixteen to date, detecting the different proteins that comprise each species using the technique of mass spectrometry. Studies are conducted in parallel to discover the biochemical pathways by which they are assembled, and the processes they mediate. This has led to the discovery of species that have antioxidant and anti-inflammatory activities, and another that protects humans against the organism that causes Trypanosomiasis, better known as African sleeping sickness. It has also been found that the removal of chemically injurious fatty substances from the retina involves HDL, leading to important new insights that can be applied to understanding macular degeneration, the leading cause of blindness in people over fifty years of age in the U.S.

Another goal in this laboratory is the discovery of genes related to the development of heart attacks and stroke. To accomplish this, a very large collection of human DNA, approaching 30,000 individual samples, has been assembled by the group. Each sample is accompanied by an extensive clinical history. Over twelve thousand genes have been studied thus far. Variations in twenty-one genes have now been found to be associated with heart attack and four genes have been linked to stroke. Because risk genes may interact with one another, the group is collaborating with the Los Alamos National Laboratory, using its supercomputers to develop new mathematical formulas for accomplishing this challenging task. Discovery of the genes that are linked to heart attack and stroke is expected to lead to new strategies for prevention and treatment of those diseases. Other targets of the genetic research by this group that are related to heart disease are diabetes, HDL deficiency states, other lipoprotein disorders, and macular degeneration. Six previously unrecognized diseases caused by defective genes have been discovered in this effort.

Thomas B. Kornberg, Ph.D.
Professor and Vice Chair of Biochemistry & Biophysics

Research Interests:
Developmental regulation

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

Theodore W. Kurtz, M.D.
Professor of Laboratory Medicine

Research Interests:
Molecular genetics of complex disease, animal models of hypertension and the metabolic syndrome, transcription modulating drugs

Summary:
Hypertension (high blood pressure) affects 60 million people in the United States and is a major cause of stroke, kidney failure, and heart disease. Patients with hypertension are also at increased risk for diabetes and often have multiple risk factors for cardiovascular disease in addition to increased blood pressure. Our research is designed to shed light on why hypertension and the associated risks for diabetes and cardiovascular disease run in families. The results of these genetic studies are used to guide development of new approaches to therapy and to identify new opportunities for preventing the development of diabetes and cardiovascular disease in high risk patients.

Pui-Yan Kwok, M.D., Ph.D.
Professor of Dermatology, Henry Bachrach Distinguished Professor of Cardiovascular Genetics

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

Summary:
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. Our group developed a number of DNA analytical assays and was part of the International Haplotype Map Consortium that recently constructed the comprehensive genetic (haplotype) maps of the human genome with close to a million markers. This map is freely available to all researchers to map genes involved in common human diseases.

Currently, we are developing efficient methods for molecular haplotyping and DNA sequencing. We are applying state-of-the-art molecular genetic tools to identify genetic factors associated with diverse complex human traits such as longevity, hypertension, sudden cardiac arrest, hemorrhagic stroke, psoriasis, lupus, and kidney transplantation outcome. We are also conducting studies to identify genetic factors associated with drug response to chemotherapy in colon cancer

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

Research Interests:
Role of inflammation in asthma; mucus hypersecretion

Summary:
Dr. Lazarus is the Principal Investigator and Co-Investigator of the National Heart, Lung & Blood Institute's COPD Clinical Research Center at UCSF and Asthma Clinical Research Center at UCSF, respectively. Our research thus focuses on these two diseases.

Asthma affects 5-10% of the US population, and asthma mortality has increased for several decades. Our laboratory has helped to examine some of the issues that determine how and why different patients with asthma respond differently. We have examined some of the genetic factors that influence response to standard therapy and have found that a significant proportion of the general population has a specific genetic mutation that is associated with a poor response. We have found also that asthmatics who smoke do not respond to steroids as well as non-smokers. We are examining specific 'predictors' of response, which if successful will make it feasible to tailor therapy individually for each patient.

COPD (chronic obstructive pulmonary disease) is comprised of chronic bronchitis and emphysema and almost always occurs as a result of cigarette smoking. It is the 4th leading cause of death in the United States, and is expected to be the 3rd leading cause of death worldwide by 2020. Other than smoking cessation and oxygen therapy, no intervention has been shown to change the natural history of this disease. We are examining ways to prevent the exacerbations that contribute to progressive loss of lung function. In addition, based on observations made in our laboratory a number of years ago in studies of arachidonic acid metabolism in isolated mastocytoma cells, we are testing whether inhibition of a specific part of this metabolic pathway will speed the resolution of COPD exacerbations, and decrease the duration of hospitalizations for this disease.

Mary J. Malloy, M.D.
Clinical Professor of Pediatrics and Medicine

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

Summary:
Because it has been found that faulty transport of cholesterol and other lipids is an underlying element in the development of arteriosclerosis, elucidation of molecular mechanisms involved in cholesterol transport has been a major goal of this group. This has led to the identification of previously unidentified proteins that participate in the process. Certain complexes of cholesterol and other fatty substances with proteins (lipoproteins) are known to convey cholesterol to the artery wall to initiate the formation of diseased areas (plaques) that can eventually lead to occlusion of arteries serving the heart or brain. Others (High Density Lipoproteins, HDL) have the task of removing cholesterol to protect the arteries. Understanding how HDL accomplish this task requires the discovery and characterization of previously unknown molecular complexes. Whereas it was thought that there were two species of HDL, work by this group has identified sixteen to date, detecting the different proteins that comprise each species using the technique of mass spectrometry. Studies are conducted in parallel to discover the biochemical pathways by which they are assembled, and the processes they mediate. This has led to the discovery of species that have antioxidant and anti-inflammatory activities and another that protects humans against the organism that causes Trypanosomiasis, better known as African sleeping sickness. It has also been found that the removal of chemically injurious fatty substances from the retina involves HDL, leading to important new insights that can be applied to understanding macular degeneration, the leading cause of blindness in people over fifty years of age in the U.S.

Another goal in this laboratory is the discovery of genes related to the development of heart attacks and stroke. To accomplish this, avery large collection of human DNA, approaching 30,000 individual samples, has been assembled by the group. Each sample is accompanied by an extensive clinical history. Over twelve thousand genes have been studied thus far. Variations in twenty-one genes have now been found to be associated with heart attack and four genes have been linked to stroke. Because risk genes may interact with one another, the group is collaborating with the Los Alamos National Laboratory using its supercomputers to develop new mathematical formulas for accomplishing this challenging task. Discovery of the genes that are linked to heart attack and stroke is expected to lead to new strategies for prevention and treatment of those diseases. Other targets of the genetic research by this group that are related to heart disease are diabetes, HDL deficiency states, other lipoprotein disorders, and macular degeneration. Six previously unrecognized diseases caused by defective genes have been discovered in this effort.

Gail R. Martin, Ph.D.
Professor of Anatomy

Research Interests:
Function of the FGF family in early mammalian development; establishment of the vertebrate body plan during gastrulation

Summary:
The Martin lab is interested in understanding the mechanisms that control the early steps in organogenesis in the vertebrate embryo, and the subsequent outgrowth and patterning of the developing organs. We are particularly interested in the roles played by members of the Fibroblast Growth Factor (FGF) family of signaling molecules and their antagonists in these processes.

Our approach to elucidating a particular gene's function is to determine the consequences of perturbing its expression during mouse development. To accomplish this we produce loss- and gain-of-function alleles of the genes of interest and study the consequences of eliminating or increasing their expression in the embryo. Using this approach we have demonstrated that FGF signaling is essential for cell survival during the early development of the brain, kidney, limbs, and other organs. Recently, we have found that eliminating Sprouty gene expression, which essentially increases FGF signaling, has profound effects on the development of the heart and lungs.

Michael A. Matthay, M.D.
Professor of Medicine and Anesthesia

Research Interests:
Alveolar epithelial transport under normal and pathologic conditions

Summary:
Our research program is focused on discovering new treatments that will improve clinical outcomes in patients with acute respiratory failure from pulmonary edema and acute lung injury. Our work includes experimental studies as well as human-based studies that are designed to learn more about the pathogenesis of acute respiratory failure and to test potential new therapies. Our work is supported primarily by grants from the National Heart, Lung, and Blood Institute.

Donald M. McDonald, M.D., Ph.D.
Professor of Anatomy

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, Ph.D.
Professor of Anatomy, Camilla and George D. Smith Distinguished Professorship in Science and Medicine

Research Interests:
Morphogenesis; developmental regulation of organogenesis

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

Daniel L. Minor, Ph.D.
Assistant Professor of Biochemistry & Biophysics

Research Interests:
Membrane proteins; potassium channels, calcium channels

Summary:
An electrical impulse drives each heartbeat. Generation of such signals requires the concerted action of ion channel proteins and the molecules that modulate their activity. Together, these proteins form the machinery that allows ions such as sodium, potassium, and calcium to move into and out of cells to make electrical signals in the heart and brain. Our lab is interested in understanding the fundamental molecular architecture of ion channels. This information is essential for understanding how they work, for developing new therapeutics to control their functions, and to understand how disease causing mutations cause problems such as arrythmias, epilepsy, and deafness. Despite decades of study by functional methods, a scarcity of high-resolution structural information and a lack of specific inhibitors for many types of channels limit our knowledge of how these molecules work. Understanding ion channels ultimately requires a high-resolution structural description of the channel proteins, their regulatory factors, and the conformational changes that accompany channel action. We are approaching this problem from the perspective of structural biology. Because channels are membrane proteins, a difficult class to investigate with any single structural technique, our efforts are directed at a multidisciplinary approach that involves both genetic, biochemical, electrophysiological, and X-ray crystallographic approaches for studying ion channel structure and function.

Keith E. Mostov, M.D., Ph.D.
Professor of Anatomy and Biochemistry & Biophysics

Research Interests:
Polarized epithelial membrane traffic and epithelial morphogenesis.

Summary:
How do individual cells organize to form a multicellular tissue? An individual cell can exhibit many different behaviors - proliferation, migration, adhesion, polarization, differentiation, and death. But to build a tissue, a population of cells must coordinate these individual behaviors across space and time. Little is understood about the mechanisms that orchestrate the actions of single cells during morphogenesis. To analyze these issues, we are studying how epithelial cells form three-dimensional organs. Epithelia are coherent sheets of cells that form a barrier between the interior of the body and the outside world. Internal epithelial organs contain two types of building blocks, cysts and tubules. Our experimental strategy uses culture of epithelial cells in a three-dimensional extracellular matrix. Single cells plated in matrix grow to form hollow cysts lined by a monolayer of cells. We have discovered a pathway containing the small GTPase, rac1, alpha1-beta3 integrin, and laminin, which coordinates cell polarity, so that apical surfaces of the cells are all oriented towards the cyst lumen. Cysts are remodeled into by growth factors, which cause transient dedifferentiation and migration, followed by redifferentiation into polarized epithelial cells lining the tubule.

Spatial asymmetry is fundamental to the structure and function of most eukaryotic cells. A basic aspect of this polarity is that the cell's plasma membrane is divided into discrete domains. The best studied and simplest example of this occurs in epithelial cells, which line exposed body surfaces. Epithelial cells have an apical surface facing the outside world and a basolateral surface contacting adjacent cells and the underlying connective tissue. These surfaces have completely different compositions. Epithelial cells use two pathways to send proteins to the cell surface. Newly made proteins can travel directly from the trans-Golgi network (TGN) to either the apical or basolateral surface. Alternatively, proteins can be sent to the basolateral surface and then endocytosed and transcytosed to the apical surface. We are studying the machinery that is responsible for the specificity and regulation of polarized membrane traffic in epithelial cells. I will discuss several recent results.

1. The SNARE hypothesis provides a unified model for how intracellular vesicular targeting and fusion work. Proteins on transport vesicles, known as v-SNAREs, pair with corresponding t-SNAREs on target membranes, leading to vesicle fusion. The correct pairing of particular v- and t-SNAREs can provide a mechanism for specificity of targeting and fusion. Polarized epithelial cells are an ideal system in which to test the role of SNAREs in specificity, as these cells contain two plasma membrane targets, the apical and basolateral surfaces, as well as multiple classes of vesicles traveling to each surface. We have found that that the t-SNARE syntaxin 3, is involved with transport to the apical surface, while the related t-SNARE, syntaxin 4, is utilized for transport to the basolateral surface.

2. The polymeric immunoglobulin receptor (pIgR) transcytoses IgA from the basolateral to the apical surface. Transcytosis is stimulated by ligand binding. Binding of IgA causes dimerization of the pIgR, which leads to activation of a non-receptor tyrosine kinase, p62Yes. Mice knocked out for this kinase are deficient in IgA transport. Phosphatidylinositol-specific phospholipase C gamma is activated, resulting in production of DAG and IP3. The DAG activates protein kinase Ce, which stimulates transcytosis. The IP3 raises intracellular free calcium, which also stimulates transcytosis. Stimulation of transcytosis also involves the small GTPase, rab3b, which directly interacts with the pIgR.

3. When epithelial cells, such as MDCK cells, are plated in a 3 dimensional collagen matrix, the cells form hollow, polarized cysts with the apical surface facing the lumen of the cyst. Overexpression of a dominant negative form of the small GTPase, rac, retards lumen formation and leads to a partial reversal of polarity, with the apical surface oriented towards the outside of the cyst. Growth of the cysts laminin rescues this phenotype, indicating that interfering with rac function interferes with the ability of the cell to assemble, laminin, which normally provides a spatial cue.

4. When collagen-grown cysts are stimulated with hepatocyte growth factor (HGF), the cysts develop branching tubules, providing a simple model system for studying tubulogenesis. The exocyst is an eight-subunit complex involved in targeting transport vesicles to specific regions of the plasma membrane. We have found that HGF treatment causes the exocyst to relocalize from the region of the tight junction to the growing tubule, indicating that new membrane is being directed to the tubule. Overexpression a subunit of the exocyst, hSec10, causes the cysts to elaborate an increased umber of tubules, indicating a direct connection between membrane traffic and tubulogenesis.

Jay A. Nadel, M.D.
Professor of Medicine and Physiology

Research Interests:
Signaling mechanisms in airway epithelium

Summary:
Inhaled bacteria and viruses, as well as irritants such as cigarette smoke, occupational hazardous materials and allergens, are deposited in the airways and result in inflammatory changes. The airway epithelium attempts to defend the organism by mounting defenses, and the airway epithelial surface becomes the 'battlefront' of interaction between the 'invaders' and the epithelial 'defenses.' How does the surface epithelium mount defensive responses? We have shown that in airway epithelium activation of epidermal growth factor receptor (EGFR) leads to the production of mucins, interleukin-8 (a potent neutrophil chemoattractant), and COX2 and cyclooxygenase products. Thus, neutrophils are recruited to the airway lumen, where they can ingest and kill invading bacteria. Subsequently, the secreted mucins trap the bacteria-laden neutrophils and assist in their clearance via cough and mucociliary clearance. How are diverse epithelial cell outcomes governed? EGFR activation is known to be involved in epithelial cell migration, multiplication and differentiation. We have shown that EGFR activation increases mucin production markedly in dense, but not sparse, cultures. Further, we found that the cell surface adhesion molecule, E-cadherin, promotes EGFR- mediated mucin production in a cell density- and cell cycle-dependent fashion via a protein tyrosine phosphatase-dependent EGFR dephosphorylation. Thus, cell surface signaling is responsible for EGFR-dependent cell differentiation. Because the first contact of environmental stimuli (e.g. bacterial products) with the airways occurs at the epithelial luminal surface, we examined potential epithelial molecules capable of intercepting invaders. Airway epithelial cells express EGFR proligands attached to the epithelial luminal surface. We found that activation of metalloprotease TACE causes shedding of EGFR ligand. The released ligand binds to and activates EGFR. This provides a powerful autocrine signaling pathway. TACE is activated by reactive oxygen species (ROS). We discovered that Duox1, a dual oxidase present on the surface of airway epithelial cells, plays a critical role in EGFR activation by releasing ROS, activating TACE, releasing EGFR proligand, causing EGFR activation.

Charles P. Ordahl, Ph.D.
Professor of Anatomy

Research Interests:
Regulation of gene expression in early embryonic cardiac and skeletal muscle development

Summary:
Our lab is studying the epigenetic changes that direct embryonic cells to form muscle. Molecular studies have identified protein-DNA interactions that govern gene derepression during myoblast differentiation. Experimental embryological methods have allowed us to identify the place and timing of the decision process in vivo. Our current efforts are directed towards the control of the myoblast decision to differentiate through small molecule pharmacology.

Robert E. Pitas, Ph.D.
Professor of Pathology; Senior Investigator, Gladstone Institute of Cardiovascular Disease, Gladstone Institute of Neurological Disease

Research Interests:
Lipoprotein metabolism in vivo and in vitro; role of lipoproteins in the development of atherosclerosis; lipoprotein receptors and atherosclerosis

Summary:
Elevated low density lipoprotein (LDL) cholesterol is the best-known, but not the only, risk factor for heart disease. High levels of lipoprotein(a) [Lp(a)] are also atherogenic. Plasma Lp(a) levels in excess of 30 mg/dl are associated with atherosclerosis and an increased risk of heart attack and stroke. Research into the role of Lp(a) in these pathologies has been hampered by the lack of a suitable animal model with high-level Lp(a) expression.

To address this problem, we developed transgenic mice with high-level expression of Lp(a). In Lp(a), apolipoprotein(a) [apo(a)], a plasminogen-like glycoprotein, is covalently linked to apoB-100, the protein component of LDL. First, we produced mice expressing apo(a) and crossed them with mice expressing human apoB-100. Using an antibody that detects oxidized phospholipids and oxidized phospholipid protein adducts, we made the interesting discovery that Lp(a) in plasma of these mice contained oxidized phospholipids, whereas LDL did not.

Oxidized LDL is thought to contribute to the development of atherosclerosis. LDL that is retained in the artery wall undergoes oxidative modification with resultant detrimental effects. This oxidized LDL apparently is not released or does not accumulate in plasma. Oxidized phospholipids in LDL are partially responsible for the uptake of lipoproteins by cells, which leads to foam-cell formation and the release of cytokines from cells, resulting in monocyte recruitment to the artery wall and in the proliferation of smooth muscle cells.

Our work is focusing on determining if oxidized phospholipids contribute to the atherogenicity of the Lp(a). Our preliminary data suggest that the Lp(a) in these mice are more atherogenic than similar levels of plasma LDL. However, it is not at all clear why plasma Lp(a) contains oxidized phospholipid and LDL does not. What is the source of the oxidized phospholipid? How does it affect the properties of Lp(a)? These new mouse models are currently being used to study these and other questions related to Lp(a), oxidized phospholipid, and atherogenesis.

Jeremy F. Reiter, M.D., Ph.D.
Assistant Professor

Research Interests:
How cells communicate with each other.

Summary:
Eukaryotic cilia and flagella are cellular structures familiar to schoolchildren everywhere for the elegant swath they cut as they propel protozoa through pond water. Less well recognized is the fact that a single immotile cilium is present on almost every type of vertebrate cell. These so-called primary cilia were discovered more than a century ago and, yet, their functions remain largely unexplored. It is now becoming clear that the primary cilium plays important roles in both development and disease. Perhaps its most dramatic function is in the kidney Ð ciliary defects cause polycystic kidney disease, the most common life-threatening monogenic illness. Primary cilia also have roles in sensing environmental information. Photoreceptors and odorant receptors function on primary cilia, and primary cilia are essential for sound reception. Therefore, it is not much of an exaggeration to say that we see, smell and hear through cilia.

Our work suggests that cilia also function as critical mediators of intercellular signals during development. One crucial role is in the coordination of the Hedgehog signal transduction pathway. Hedgehog signals are essential regulators of embryonic patterning and cell proliferation, and defects in Hedgehog signaling are important causes of both birth defects and many cancers. We are currently extending this work by asking a few fundamental questions about primary cilia:

Do cilia transduce intercellular signals other than Hedgehog?

How do cilia interpret signals essential to vertebrate development?

Do cilia participate in Hedgehog-mediated oncogenesis?

How do cells regulate whether they form a cilium?

This work has begun to suggest that the primary cilium is an organelle dedicated to signal transduction, somewhat analogous to a cellular antenna. We hope that our current endeavors will reveal how this antenna interprets the signals required for normal development and homeostasis, and how malfunctions in the antenna contribute to cancer and other important human diseases.

Steven D. Rosen, Ph.D.
Professor of Anatomy

Research Interests:
Molecular mechanisms of leukocyte-endothelial interactions

Summary:
There are a number of ' inflammatory diseases' in which white blood cells in the blood migrate into tissues and produce damage. Two of the most serious diseases of this kind are rheumatoid arthritis (RA) and bronchial asthma. The invading white blood cells damage the tissue, for example by degrading cartilage in joints or by producing substances that cause the airways to narrow in asthma. We are studying how white blood cells migrate from the blood into these tissue sites. Under normal circumstances, white blood cells are an essential part of the body's defense against infections and diseases and they patrol blood and return to specialized organs (such as lymph nodes) where an immune response can be initiated. This process occurs in response to chemical signals instructing the white blood cells to enter these organs by exiting through blood vessels that supply the organs.

We have identified novel enzymes that are critical to producing the chemical signals which recruit white blood cells to lymph nodes under normal conditions. Our work indicates that these same enzymes are also involved in attracting white blood cells to the joints or lungs, thereby causing the painful inflammation associated with arthritis or the difficulty in breathing for asthmatics. Interfering with these enzymes or the chemical signals they produce will block the migration of white blood cells to these tissues and thereby prevent the damage that they produce. To study arthritis, we are using a mouse model of RA in which white blood cells invade and damage the joints. Using recombinant DNA technology, we have generated mice lacking the enzymes. Understanding the invasion processes in these mice may help us to explain the analogous processes in RA. With this understanding may come new therapeutic approaches for treatment of this condition. We are also studying asthma in sheep models of this disease looking for interventions that block the chemical signals which attract white blood cells to the lungs. Success here may lead to the development of new drugs to treat asthma, a disease of increasing incidence in the world.

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).

Robin M. Shaw, M.D., Ph.D.
Assistant Professor of Medicine

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. For the heart to work properly, the function of millions of individual heart cells needs to be coordinated each second to act in synchrony. In the normal heart, a biological electrical system exists to coordinate the heart cells and consists of ion channels that regulate the flow of sodium, calcium and potassium ions in and out of cells. The collective movement of these molecules in and out of these ion channels creates the signals for the cells to contract. In the diseased heart, damage from blocked heart arteries leads to improper cellular expression of the ion channels, which results in dangerous heart rhythms such as the 'flatline' of sudden cardiac death. In this situation, the biological electrical system is 'short circuited', and millions of cells are contracting randomly, leaving a nonworking pump. There are 200,000 to 400,000 cases of sudden cardiac death in the United States each year. In addition, cumulative damage to the heart over time can result in the poorly coordinated and weakened contraction of congestive heart failure, which affects five million Americans. For these reasons, we are very interested in ion channel regulation in both normal and damaged heart cells. We use a cell biology based approach to study the movement of the proteins that form the channels as they travel from their site of formation to their placement and specific locations on the heart cell membrane. Specific projects in the laboratory involve studying how cells lose communication with each other and with their signals to contract by altering the delivery of ion channels to their proper functional subregion on the cell membrane. The ultimate goal is to use the insights gained by these studies to develop ion channel targeted therapeutic interventions that decrease the incidence and impact of sudden cardiac death and heart failure.

Dean Sheppard, M.D.
Professor of Medicine

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

Summary:
Our lab studies how a family of proteins (integrins) that provide cells with detailed information about their surroundings contributes to the development of common lung diseases. The lab has made lines of

CVRI Scientists

Kaveh Ashrafi, Ph.D. Assistant Professor

Diane L. Barber, Ph.D. Professor of Cell & Tissue Biology

Harold S. Bernstein, M.D., Ph.D. Associate Professor of Pediatrics

Brian L. Black, Ph.D. Associate Professor of Biochemistry & Biophysics

Paul D. Blanc, M.D. Professor Medicine; Division Chief, Occupational Medicine

Homer A. Boushey , M.D. Professor of Medicine; Division Chief, Allergy & Immunology

V. Courtney Broaddus, M.D. Professor of Medicine

James K. Brown, M.D. Associate Professor of Medicine

Benoit G Bruneau, Associate Professor

George H. Caughey, M.D. Professor of Medicine; Chief, Pulmonary & Critical Care Medicine Section, VAMC

Harold A. Chapman, M.D. Professor of Medicine; Chief, Division of Pulmonary and Critical Care Medicine

Israel F. Charo, M.D. , Ph.D. Senior Investigator, Gladstone Institute of Cardiovascular Disease

Kanu Chatterjee, M.D. Ernest Gallo Distinguished Professor of Medicine

Pao-Tien Chuang, M.D. , Ph.D. Associate Professor of Biochemistry & Biophysics

Ronald I. Clyman, M.D. Professor of Pediatrics

Bruce R. Conklin, M.D. Associate Investigator, Gladstone Institute of Cardiovascular Disease

Shaun R. Coughlin, M.D., Ph.D. Professor of Medicine and Cellular & Molecular Pharmacology; Distinguished Professorship in Cardiovascular Biology & Medicine; CVRI Director

Rik M. Derynck, Ph.D. Professor of Cell & Tissue Biology

Leland G. Dobbs, M.D. Adjunct Professor of Medicine and Pediatrics

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

Joanne N. Engel, M.D., Ph.D. Associate Professor of Medicine and Microbiology & Immunology

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

John Vincent Fahy, M.D. Professor of Medicine

Robert V. Farese, Jr., M.D. Senior Scientist, J. David Gladstone Institutes, Professor of Medicine and of Biochemistry & Biophysics

Christopher J. Fielding, Ph.D. Professor of Physiology

Phoebe Fielding, Ph.D. Adjunct Professor of Medicine

Jeffrey R Fineman, M.D. Professor of Pediatrics

Stanton A. Glantz, Ph.D. Professor of Medicine

William Grossman, M.D. Professor of Medicine; Chief, Division of Cardiology

Samuel Hawgood, M.B., B.S., M.D. Professor and Chair of Pediatrics

Holly A. Ingraham, Ph.D. Professor of Physiology

Lily Y. Jan, Ph.D. Professor of Physiology and Biochemistry & Biophysics; Investigator, Howard Hughes Medical Institute; Jack and DeLoris Lange Endowed Chair of Physiology and Biophysics

Yuet W. Kan, M.D. Professor of Medicine and Laboratory Medicine; Louis K. Diamond Professor of Hematology

John P. Kane, M.S., M.D., Ph.D. Professor of Medicine and Biochemistry & Biophysics

Thomas B. Kornberg, Ph.D. Professor and Vice Chair of Biochemistry & Biophysics

Theodore W. Kurtz, M.D. Professor of Laboratory Medicine

Pui-Yan Kwok, M.D., Ph.D. Professor of Dermatology, Henry Bachrach Distinguished Professor of Cardiovascular Genetics

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

Mary J. Malloy, M.D. Clinical Professor of Pediatrics and Medicine

Gail R. Martin, Ph.D. Professor of Anatomy

Michael A. Matthay, M.D. Professor of Medicine and Anesthesia

Donald M. McDonald, M.D., Ph.D. Professor of Anatomy

Takashi Mikawa, Ph.D. Professor of Anatomy, Camilla and George D. Smith Distinguished Professorship in Science and Medicine

Daniel L. Minor, Ph.D. Assistant Professor of Biochemistry & Biophysics

Keith E. Mostov, M.D., Ph.D. Professor of Anatomy and Biochemistry & Biophysics

Jay A. Nadel, M.D. Professor of Medicine and Physiology

Charles P. Ordahl, Ph.D. Professor of Anatomy

Robert E. Pitas, Ph.D. Professor of Pathology; Senior Investigator, Gladstone Institute of Cardiovascular Disease, Gladstone Institute of Neurological Disease

Jeremy F. Reiter, M.D., Ph.D. Assistant Professor

Steven D. Rosen, Ph.D. Professor of Anatomy

Melvin M Scheinman, M.D. Professor

Robin M. Shaw, M.D., Ph.D. Assistant Professor of Medicine

Dean Sheppard, M.D. Professor of Medicine