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Vascular biology and atherothrombosis

Metabolism, obesity and metabolic diseases

Developmental biology and congenital anomalies

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Ion channels and arrhythmias

Muscle biology and heart failure

Prediction and prevention of cardiovascular disease

Advanced technologies

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.

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.

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.

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.

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.

Steven D. Rosen, Ph.D. Professor of Anatomy Research Interests: Molecular mechanisms of leukocyte-endothelial interactions Summary: There are a number of Ò inflammatory diseasesÓ 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.

Rong Wang, Ph.D. Assistant Professor of Surgery Research Interests: Arteriovenous specification, arteriogenesis, angiogenesis, Notch, blood vessel development, cancer and ischemia Summary: Understanding what controls blood vessel development and identity is an important focus of current biomedical research because of its broad implication in cardiovascular disease, cancer, stroke and many other human diseases. Much of the current research on blood vessel growth, angiogenesis, is centered on capillaries, the small blood vessels that connect the arterial and venous networks. The molecular signals that direct a newly forming vessel to become an artery or a vein are poorly understood. Similarly, the mechanisms responsible for development, maintenance and re-growth of arteries and veins are still largely a mystery. The first genetic component of arteriovenous (AV) specification was recently discovered. During embryonic development, ephrinB2, a cell surface protein, is specifically expressed in the developing arteries. The gene encoding this protein, ephrinB2, is linked to another gene, Notch, which encodes a transmembrane receptor protein, Notch, that is an upstream member of the same signaling pathway. Our laboratory is focused on determining the cellular and molecular mechanisms underlying Notch- and ephrinB2-mediated arterial growth and differentiation. We study Notch- and ephrinB2-mediated arterial growth and differentiation in three contexts: development, cancer and revascularization (development of new blood vessels or expansion of existing blood vessels) following ischemia (stroke). In addition, we look at gain-of-function (protein overexpression) and loss-of-function (gene deletion) mutations. The overall goal of our research is to identify novel drug targets and develop new therapies for cancer, ischemia, peripheral arterial disease, heart attack and stroke, some of the world's most common and devastating diseases.

Orion D. Weiner, Ph.D. Assistant Professor of Biochemistry & Biophysics Research Interests: Cell polarity and chemotaxis 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 ÒcompassÓ 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. Professor of Medicine and Chief, Rheumatology Division; UCSF Investigator, Howard Hughes Medical Institute Research Interests: Signal transduction; autoimmunity Summary: The response of T lymphocytes to antigen presents a unique opportunity to study how complex molecular interactions between cells can lead to cell differentiation and proliferation. We are interested in understanding how T and B cell receptors involved in antigen recognition can initiate signal transduction events that regulate cell responses. We know that such receptors functionally interact with tyrosine kinases and phosphatases, enzymes that regulate protein phosphorylation, to induce signaling pathways that regulate gene expression. We are interested in understanding how the molecules in these pathways are regulated and how they control cellular responses in development, in normal immune responses and in autoimmunity.

Ethan J Weiss, M.D. Assistant Professor of Medicine Research Interests: Genetic regulation of blood clotting in mice; sex differences in blood clotting. 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 of Anatomy 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. James P. Livingston Professor and Vice Chair; Department of Anesthesia and Perioperative Care; Professor of Neurological Surgery and Neurology; Director, Center for Cerebrovascular Research 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: Despite rapid advances at several levels-molecular biology, computational biology, bioengineering, clinical physiology, epidemiology, and clinical trials-cerebrovascular disease remains a significant medical and socioeconomic challenge that often defies traditional research paradigms. Our broad goal is to improve understanding of contemporary issues and problems in cerebrovascular disease using an integrative strategy. This is predicated on translational, interdisciplinary approaches to provide a basis for more effective, safe, and humane treatment of cerebrovascular diseases. Consistent with this goal is our commitment to provide the opportunity for students and faculty to pursue all levels of pre-doctoral, post-doctoral, and post-graduate training.