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Vascular biology and atherothrombosis

Metabolism, obesity and metabolic diseases

Developmental biology and congenital anomalies

Pulmonary biology and disease

Ion channels and arrhythmias

Muscle biology and heart failure

Prediction and prevention of cardiovascular disease

Advanced technologies

Elias H Botvinick, M.D. Professor In Residence Research Interests: Nuclear medicine, nuclear cardiology, PET/CT, MRI, CT, cardiac cardiology, echocardiology, nuclear magnetic resonance, cardiovascular imaging, stress testimg, heart, myocardial perfusion, scintigraphy, coronary, sychrony, sychronization Summary: My research centers on a collaborative effort to develop noninvasive imaging methods for the identification and evaluation of cardiac anatomy and pathophysiology, and apply them to the diagnosis, risk stratification and monitoring of clinical disease. The work is centered on nuclear medicine methods, PET and SPECT, as well as echocardiography, MRI, and CT.

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

Michael S Conte, M.D. Chief, Vascular Surgery Research Interests: Aortic reconstruction, carotid artery disease, lower extremity arterial occlusive disease, diabetic vascular disease Summary: Our laboratory studies the healing process in blood vessels which currently limits the long term success of procedures like angioplasty and bypass surgery. Our goals are to develop new drug and molecular therapies to prevent failures due to vessel re-narrowing, and to better identify patients at increased risk.

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

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

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

Stanton A Glantz, Ph.D. Professor of Medicine Research Interests: Mechanics of cardiac function (experimental and theoretical); environmental tobacco smoke and tobacco control policy Summary: Dr Glantz studies the effectiveness of different tobacco control strategies, particularly in the context of large state-run tobacco control programs, how the tobacco industry works to systematically distort the scientific process and animal and human studies of the effects of passive smoking on the heart.

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

John P Kane, M.S., M.D., Ph.D. Prof Research Interests: Structure and function of lipoproteins; genetic determinants of arteriosclerosis Summary: The Kane laboratory focuses on the discovery of the native structures of lipoproteins ( proteins that carry cholesterol so that we can better understand how they are involved in the development of heart disease and stroke. We are also active in the discovery of alterations in genes that lead to heart disease and stroke.

Robert W Mahley, B.S., Ph.D., M.D. Director Research Interests: I. Plasma lipoprotein metabolism ¥ Hepatic and intestinal origin of plasma lipoproteins; ¥ Apolipoprotein structure and function, especially apolipoprotein (apo) E and apoB; ¥ Characterization of cell surface receptors for lipoproteins; ¥ Role of the liver in cholesterol homeostasis. II. Relationship of plasma lipoproteins to the development and progression of atherosclerosis ¥ Role of diet in progression of coronary artery heart disease; ¥ Effect of apoE production in the artery wall on inhibition of atherogenesis. III. Role of apoE in the nervous system ¥ Effect on peripheral nerve injury and repair; ¥ Role in the pathogenesis of Alzheimer's disease; ¥ Effect on neuronal cytoskeleton. IV. Turkish Heart Study ¥ Director of epidemiological study to determine the risk factors responsible for coronary artery disease in Turkey; ¥ Characterization of genetic polymorphisms responsible for low HDL-C levels and metabolic syndrome in Turks; ¥ Co-director of physician continuing education program for Turkish doctors and medical students in the area of cardiovascular disease. Summary: My research has focused on the structure and function of apolipoprotein (apo) E, specifically its critical role in cholesterol homeostasis and atherosclerosis and, more recently, in Alzheimer's disease and neurodegeneration. ApoE regulates the clearance of plasma lipoproteins by mediating their binding to lipoprotein receptors and is also involved in peripheral nerve regeneration, lipid transport in the nervous system, and cytoskeletal stability and neurite extension and remodeling. A goal of our research is to develop a drug that will block the detrimental effects of apoE4 in cardiovascular and neurodegenerative disorders.

Michael J Mann, M.D. Research Interests: 1. Molecular/cellular biology and molecular genetics of atherosclerosis and heart failure. 2. Development of hybrid surgical and molecular/cellular therapies for heart disease. 3. Stem and progenitor cell transplantation for cardiovascular regeneration. 4. Cardiovascular tissue engineering. 5. Reduction to clinical practice of current methods in genetic, molecular and cellular disease intervention. 6. Novel targeted molecular therapies for lung cancer. 7. Molecular profiling of cancers for personalized medicine. 8. Development of novel methods of in vivo/ex vivo gene therapy and gene transfer. 9. Novel approaches to therapeutic neovascularization for coronary and peripheral ischemic disease. 10. Cardiovascular cell cycle biology. 11. Myocardial gene therapy. Summary: Dr. Mann's research focuses on the molecular and cellular biology of heart disease with an emphasis on practical ways to develop new treatments for heart failure. These involve potential gene and molecular therapies, combinations of molecular and cell-based treatments with surgical reconstruction, and evaluation of novel materials for the development of bioartificial replacements of lost or damaged heart tissue.

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

Michael A Matthay, M.D. Professor In Residence Research Interests: Alveolar epithelial transport under normal and pathologic conditions. Resolution of pulmonary edema Mechanisms of Acute Lung Injury Summary: My research program is focused on identifying mechanisms responsible for fluid transport across the alveolar epithelium using cell, molecular, and in vivo models. In addition, our group is focused on understanding the mechanisms responsible for the development and resolution of pulmonary edema and acute lung injury in critically ill patients with acute respiratory failure. The studies include experimental and human-based studies designed to understand the pathogenesis of acute respiratory failure and to test potential new therapies. The work is supported primarily by grants from the National Heart, Lung, and Blood Institute.

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

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

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

Paul C Simpson, M.D. Prof In Rsdn Research Interests: Molecular & cellular mechanisms of myocardial hypertrophy and heart failure Adrenergic receptors, signaling, and drug development Summary: Dr. Simpson is working to develop new drugs to treat heart failure, one of the most common causes of hospitalization and death in the USA and Western World. He has recently identified a promising drug target, alpha-1-adrenergic receptors, and is working to translate this into clinical use.

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

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

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

Orion D Weiner, Ph.D. Asst Professor In Residence Research Interests: Cell polarity, chemotaxis, actin cytoskeleton, cell signaling, cell migration, microscopy, biochemistry, neutrophils, systems biology, self-organization, inflammation, Rac, PI3Kinase, WAVE complex. Summary: Proper movement in response to cues from the outside world is as important for single cells as it is for drivers on a busy highway. If cues are misinterpreted or the movement goes awry, terrible accidents ensue, the delicate wiring of the nervous system fails, single-celled organisms can`t hunt or mate, the immune system ceases to function properly, and cancer cells spread from one part of the body to another. How do single cells, without the benefit of a brain, interpret the subtle micro-world of attractants and repellents to decide where to go? Our research focuses on dissecting the inner workings of the cellular "compass" used to guide cells on their journey. Because the core of the compass has been conserved over more than a billion years of evolution, we have been able to combine discoveries from yeast to humans to glimpse some rough outlines of the underlying machinery. However, many of the important connections are still missing. Our research focuses on identifying these key missing components and how they are wired together to process information with the hope that we can eventually make cells move when (and where) we want them to and stop them when we don`t.

Arthur Weiss, M.D., Ph.D. Chief of Rheumatology Research Interests: Cell Surface Molecules and Molecular Events Involved in Lymphocyte Activation Summary: Dr. Weiss studies on how the functions of cells of the immune system are regulated. The immune system protects individuals from infections and malignancies. However, it is also involved in undesirable destructive responses, such as in autoimmune and allergic diseases as well as atherosclerosis and transplant rejection.

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

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

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