Basic Science

Updated May 2015



Cardiology

Faculty name: Andrew Boyle, MD

Contact information: Phone:415-514-0827
                                    aboyle@medicine.ucsf.edu

Subspecialty/research focus: Cardiology/Interventional Cardiology and Cardiomyocyte biology

Title of research project: Apoptosis and autophagy in cardiomyocytes

 My research involves the response of cardiomyocytes to stress, such as ischemia or aging. Using laboratory and animal studies, we are investigating why and how cardiomyocytes die in response to various stimuli, in particular we study cardiomyocytes after myocardial infarction and in aging. We explore molecular, cellular and genetic aspects of cell death, cellular protection and turnover. This links very closely with stem cell function and therapy for the failing heart. In addition, we are commencing pilot observational human studies in this area.


Faculty name: Shaun R. Coughlin, MD, PhD

Contact information: Cardiovascular Research Institute
                                    University of California, San Francisco
                                    600 16th Street, Room S472D
                                    San Francisco CA 94143-2240
                                    Phone: 415 476 6174
                                    FAX: 415 476 8173
                                    Shaun.Coughlin@ucsf.edu 

Subspecialty/research focus: Cardiology/Signaling mechanisms in cardiovascular biology and disease 

Title/description of research projects:

How are the thrombi that cause most heart attacks and strokes formed? How are normal hemostatic and inflammatory responses to tissue injury triggered? The coagulation cascade generates thrombin and related serine proteases upon disruption of vascular integrity, and thrombin is a potent activator of platelets, endothelial and other cells. How does a protease like thrombin behave like a hormone to regulate the cellular behaviors? We've characterized a family of protease-activated G protein-coupled receptors (PARs) that provide an answer. Thrombin cleaves PAR1's N-terminal exodomain to unmask a new amino terminus that then serves as a tethered peptide ligand, binding intramolecularly to the heptahelical segment of the receptor to cause transmembrane signaling. PAR1 is the prototype for a family of four receptors that appear to account for most cellular responses to coagulation and other trypsin-like proteases. Our laboratory currently focuses on understanding the roles of protease and PAR signaling and, more broadly, G protein-coupled receptors in cardiovascular biology:

PARs in physiology and disease. Using mice with individual and combined PAR deficiencies, we are exploring the importance of PAR signaling in platelets, endothelial cells and other cell types in mouse models of hemostasis and thrombosis, inflammation and other processes. A current emphasis is utilizing advanced light microscopy techniques to visualize the biochemical and cellular events that mediate various stages of thrombus assembly. Early studies show that PAR signaling is unnecessary for formation of an initial juxtamural platelet thrombus but required for enlargment and propagation of such thrombi. Thus different signaling mechanisms may be important at different points in the development of a thrombus, and exploiting such differences may permit the development of safer antithrombotic drugs.

PARs in embryonic development. PAR1 signaling in endothelial cells is important for normal vascular development in the mouse embryo. Efforts to identify the specific endothelial cell behaviors involved as well as the other targets of the coagulation cascade that are important for embryonic development are in progress. PARs, specifically PAR2, also appear to contribution to neurulation. Efforts to determine what PAR2 senses biochemically and physiologically and what it regulates in this context are ongoing. This line of research will reveal new roles for protease signaling.

Sphingosine kinases in development and disease. Sphingosine-1-phosphate acts through G protein-coupled EDG receptors to regulate heart and blood vessel formation in the embryo as well as leukocyte trafficking and other important processes in the adult. The exact sources of S1P and hence when and whether it functions primarily as a hormone or as a paracrine or autocrine factor are unknown. We have generated conditional alleles for the two sphingosine kinases in mice to explore these questions.

Novel roles for G protein signaling. The studies outlined above emphasize that G protein-coupled receptors can play important roles in embryonic development. The ~350 nonodorant G protein-coupled receptors in mice and humans couple through 4 main G protein families, Gs, Gq, Gi, and G12/13. We are ablating G12/13 and Gi signaling in specific cell lineages to probe the roles of these pathways in embryonic development and other processes, then using a candidate approach to identify the receptors and ligands involved.


Faculty name: Joel Karliner, MD

Subspecialty/research focus: Cardiology/Cardioprotection

Title of research project: Cardioprotection by sphingolipids and other compounds.

Brief description: We employ a variety of genetically altered mouse models as well as rats to study mechanisms of cardioprotection by compounds such as sphingosine-1- phosphate, quinines, and PKC isoforms. Studies are performed in intact animals, isolated hearts, cell culture and isolated mitochondria. Functions that are studied include hemodynamic and infarct size responses, signaling pathways, and mitochondrial energetics. Approaches utilize echocardiography, hemodynamic measurements, and biochemical and molecular determinants of mechanisms affecting cardiac function during hypoxia/reoxygenation and free radical generation [isolated cells and mitochondria], ischemia/reperfusion injury [isolated hearts and acute studies in intact rats and mice], and chronic infarction models in intact rodents.


Faculty name: Robin Shaw, MD, PhD

Contact information: Robin.Shaw@ucsf.edu
                                    pager 443-8008    

Subspecialty/research focus: Cardiology Cardiac Electrophysiology
                                                  Cell Biology
                                                  Ion Channel Trafficking and Targeting

Title of research project: Post-Translational Trafficking of Cardiac Ion Channels

The basic function of the heart is to work as a pump, circulating blood through the lungs, brain, and body. For each successful heartbeat the activity of millions of individual heart cells must to be coordinated for them to contract in synchrony. The cardiac electrical system, based on ion channels and the flow of ions exists for this coordination. In ischemic heart, ion channels are both poorly expressed and improperly localized, which result in dangerous heart rhythms such as sudden cardiac death. There are 325,000 cases of sudden cardiac death in the United States each year. In addition, ischemia related congestive heart failure, which affects five million Americans, is due in part to altered ion channel regulation.

For these reasons, we are very interested in ion channel regulation in both normal and damaged heart cells. We recently developed a new paradigm describing the mechanism by which the ion channels are targeted from inside the cell to their proper location on the cell membrane. We are continuing a cell biology based approach to study the movement of ion channels from the time they are formed to their placement at specific locations on the cell membrane. The techniques of the lab involve live cell imaging and total internal reflection microscopy (TIRF) as well as standard immunocytochemistry and biochemistry. The goal of our research is to use the insights gained by these basic cell biological studies to develop therapeutic interventions that decrease the incidence and impact of sudden cardiac death and heart failure.


Faculty name: Paul C. Simpson, MD

Contact information: paul.simpson@ucsf.edu
                                    VAMC 111-C-8

Subspecialty/research focus: Cardiology Basic-Translational Research

Title/description of research projects:

Drug Discovery in Heart Failure

We are using heart failure models in mouse, rat, rabbit, and man (living human myocardial tissue) to test a novel potential target for prevention and treatment of cardiomyopathy and heart failure, an adrenergic receptor subtype. A variety of projects are ongoing in these models, using isolated myocytes, isolated myocardium and hearts, and intact animals, with technology from more basic (molecular biology, biochemistry, pharmacology, and immunohistology) through cardiac physiology in the intact animal (echo, telemetry, drug delivery). Projects are appropriate for someone with an interest in heart failure and/or drug discovery, and a desire to work at the lab bench.


Faculty name: Matthew L. Springer, PhD

Contact information: Division of Cardiology
                                   University of California, San Francisco
                                   513 Parnassus Avenue, Room S1136, Box 0124
                                   San Francisco, CA 94143-0124
                                   Phone (415) 502-8404
                                   matt.springer@ucsf.edu

Subspecialty/research focus: Angiogenesis, vascular biology, cardiac repair, gene therapy, cell therapy, endothelial nitric oxide synthase, cigarette secondhand smoke

Title/description of research projects: Cell therapy for myocardial infarction 

We are studying the therapeutic effects of implanting bone marrow-derived cells (BMCs) into mouse hearts after myocardial infarction (MI), using a high-resolution echocardiography approach that we developed in collaboration with Dr. Yeghiazarians to guide injections into the myocardial wall without surgery.  The echo-guided approach allows us to introduce BMCs to mouse hearts several days after MI, a time relevant to current clinical trials that is not feasible when using traditional open-chest injection approaches.  We have shown that injection of BMCs 3 days post-MI can preserve or partially restore left ventricular function.  We have also demonstrated that injection of a cell-free extract of lysed BMCs has a similar therapeutic effect, suggesting not only that BMC therapy may be beneficial by a paracrine mechanism, but also that the cells may simply die and thus deliver a bolus of therapeutic growth factors.  

We and others have found BMC therapy to be quite effective at improving cardiac function post-MI in rodents, but human clinical trials of BMC therapy have been less robust.  We have recently demonstrated in mice that regardless of the state of the recipient heart, the donor BMCs themselves are therapeutically impaired by the age and post-MI state of the donor.  This is an important point because human bone marrow cell therapy trials are autologous; that is, the patients are treated with their own cells, and those cells are thus derived from older, post-MI individuals.  In contrast, mouse model BMC therapy experiments use bone marrow harvested from one mouse and delivered to the hearts of others, and the donor mice are typically younger and healthy, a poor reflection of the clinical situation being modeled.  We have shown that BMCs from old donor mice lack therapeutic efficacy for treatment of MI, and cells from donor mice that are themselves post-MI are impaired.  In the case of donor MI, the MI causes inflammation in the heart that changes the composition of the bone marrow via interleukin-1-mediated signaling such that the harvested BMCs are in a pro-inflammatory state. 

Angiogenesis 

We are interested in the responses of adult cardiac and skeletal muscle to angiogenic signaling and gene therapy, focusing on effects of VEGF on the vasculature.  This continues Dr. Springer's pre-UCSF research aimed at understanding the response of adult tissue to exogenous VEGF gene delivery, potential deleterious effects, and potential therapeutic applications.  We are also studying potential neovascularization effects of pleiotrophin, a less-characterized growth factor, which we have shownto be a chemoattractant for circulating angiogenic cells (otherwise known as endothelial progenitor cells).  In addition, we are currently studying myocardial-specific mechanisms of angiogenesis and how microvascular endothelial cells successfully carry out the required pattern formation while subjected to the cyclical compressive forces in the heart. 

Role of NO synthase in human circulating angiogenic cell function

We are interested in the molecular basis of age- and disease-related impairment of circulating angiogenic cells (CACS; which have also been called early endothelial progenitor cells or EPCs), a heterogeneous population of cells that are thought to be involved in several aspects of angiogenesis and endothelial maintenance.  

We are studying endothelial nitric oxide synthase (eNOS)-dependent and eNOS-independent mechanisms of CAC migration toward angiogenic stimuli by VEGF and pleiotrophin, and are investigating the molecular mechanisms through which NO controls CAC migration and interactions with endothelium.  The contributions of inherent eNOS activity and oxidative stress to overall CAC function are being investigated, as are strategies to use eNOS gene therapy to modify their potential as therapeutic agents for cardiovascular disease. 

Endothelium-dependent vascular reactivity and second hand smoke

Flow-mediated vasodilation (FMD), the process by which arteries sense increased blood flow requirements, is important for maintaining cardiovascular heath and a useful prognostic indicator.  We have developed a micro-ultrasound-based approach to measure FMD in arteries of living rats, and have shown that FMD in the rat model is physiologically similar to that in humans.  The vasodilation that occurs after transient upstream arterial occlusion is dependent on hyperemic blood flow and is also dependent on eNOS activity.  We have been able to detect age-related impairment of FMD with this approach.  

We are currently using this system to study the beneficial effects of modulation of NO bioavailability on endothelial function, and how vascular function is impaired by brief exposure to low levels of cigarette second hand smoke.  

For more information, please see http://cardiolab.ucsf.edu/molcardiolab/


Faculty name: Hua Su, MD

Contact information: Phone:415-476-5626
                                    hua.su@ucsf.edu or page; 443-9193

Subspecialty/research focus: Angiogenic gene and cell therapies for myocardial infarction

Title of research project:
Angiogenic therapy has been investigated as a potential therapeutic strategy for ischemic cardiomyopathy for two decades, but there is still no product available for clinical use. The problems include short duration of action of the angiogenic factors, inadequate transduction or expression of the genes, and immune reactions against the delivery vectors. Also, uncontrolled expression of angiogenic factors may cause complications. To overcome these difficulties we used the adeno-associated viral (AAV) vector to mediate long-term angiogenic gene expression and used cardiac-specific promoter and hypoxia response element to limit the angiogenic gene expression in ischemic myocardium. We use mouse and porcine as model for our study. Our goal is to development an effective and safe angiogenic gene therapy for the treatment of ischemic cardiomyopathy.

Irreversible myocardial-injury occurs shortly after the onset of coronary occlusion. Angiogenic therapy can reduce post-infarct remodeling and improve cardiac function, but it has little effect on repairing existing scars. Transplantation of stem cells from various sources into infarcted hearts has the potential to regenerate injured myocardium. We have tested to use bone marrow derived mesenchymal stem cells (MSCs) myocardial regeneration. We noticed that the survival rate of MSCs was very low in ischemic myocardium. Thus, we proposed a strategy of combining cell therapy with angiogenic gene therapy. We hypothesized that angiogenic factors will stimulate neovascular formation in ischemic myocardium, which in turn will support transplanted stem cell survival.

Recent studies indicated that embryonic stem cells (ESCs) may be a better source for cardiac regeneration. However, none of the current methods can mediate ESC to differentiate into 100% pure cardiomyocytes. Using a mixture of differentiated cardiomyocytes and undifferentiated ESC may potentially cause tumor. We study to isolate ESC-derived cardiomyocytes by genetically labeling the human ESCs with a cardiac-specifically expressed surface marker. AAV vector will be used to deliver the genes. The purity, protein expression profile, the tumorigenicity and the regenerative ability of the selected cells will be studied.


Faculty name: Ethan J. Weiss, MD

Contact information: ethan.weiss@ucsf.edu
                                    Pager 443-9193

Subspecialty/research focus: Cardiology
                                                  Genetics of Blood Clotting
                                                  Hemostasis and Thrombosis
                                                  Sex Differences in Blood Clotting and Coagulation Proteins and Inhibitors

Title of research project:

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.


Faculty name: Lewis (Rusty) Williams, MD, PhD
                        Chairman and Founder
                        FivePrime Therapeutics
                        Adjunct Professor
                        Department of Medicine, UCSF

Contact information: rusty.williams@fiveprime.com,
                                   Phone: 415-365-5674

Title/description of research projects:

  1. Discovery of new receptors and ligands that are good targets for cancer therapy.

We have produced a unique library of over 3000 proteins including essentially all secreted proteins (ligands) and most extracellular domains of transmembrane proteins (receptors). Using a high through put automated screening system we can quickly find receptors for ligands whose receptors are unknown. This is particularly important for ligands that are linked to cancer tissue and their receptors may be drug targets. Likewise we can find ligands for "orphan" receptors. Most of the scientists at FivePrime are working directly on protein drugs and we have not had a scientist to work full time on this receptor-ligand matching project. For this reason there is an exceptional opportunity for a resident to make multiple discoveries using our system and findings New therapies for diabetes.

    2. We have discovered a protein that increases glucose uptake in muscle but not fat. When given to mice with diabetes our protein (FPT038) reduces hyperglycemia, reduces insulin levels but does not cause hypoglycemia. All of these effects appear to be favorable in the treatment of diabetes. In addition there appears to be a persistent beneficial effect many hours after the protein is cleared from the circulation. FivePrime is developing this protein as a drug. Although much is understood about FPT038 there are still unanswered scientific questions about the mechanism of its persistent effect and its apparent insulin sensitizing activity that need answering.

   3. Protein therapeutics for acute myocardial infarction

We have discovered 4 proteins that appear to protect cardiac myocytes from ischemic damage in vitro. We are interested in studies of these proteins in animal models of myocardial infarction. The goal of this work is to develop therapeutic proteins that can be used clinically to rescue myocardium during the early stages of infarction.


Faculty name: Yerem Yeghiazarians, MD

Contact information: yeghiaza@medicine.ucsf.edu
                                    office phone 415-353-3817

Subspecialty/research focus: Cardiology; Interventional Cardiology; Peripheral Vascular Disease; Vascular Biology; Cardiac Stem Cell Research

Title/description of research projects: 
After a myocardial infarction, loss of contracting heart muscle cells occurs resulting in scar formation and subsequently heart failure. Current therapies designed to treat heart attack patients in the acute setting include medical therapies and catheter-based technologies that aim to open the blocked coronary arteries with the hope of salvaging as much of the jeopardized heart muscle cells as possible. Unfortunately, despite these advances over the past 2 decades, it is rarely possible to rescue the at-risk heart muscle cells from some degree of irreversible injury and death. In addition, the delay in the time that most patients present to receive their care has been recognized as a major factor in the failure of current techniques in preventing significant cardiomyocyte injury.

Attention has thus turned to new methods of treating heart attack and heart failure patients in both the acute and chronic settings after their event. Heart transplantation remains the ultimate approach to treating end-stage heart failure patients but this therapy is invasive, costly, some patients are not candidates for transplantation given their other co-morbidities, and most importantly, there are not enough organs for transplanting the increasing number of patients who need this therapy. As such, newer therapies are needed to treat the millions of patients with debilitating heart conditions. Recently, it has been discovered that stem cells, which are early progenitor cells with the ability to direct the production of all different types of human cells, may hold the therapeutic potential for these patients. Experimental studies in both animals and humans have revealed encouraging results when stem cells are injected into the heart in the areas of myocardial infarction. These therapies appear to result in improvement in the contractile function of the heart.

Despite these promising early trials, many questions remain unanswered concerning the use of stem cells as therapy for patients with heart attack and heart failure. To answer these questions and to ultimately offer this therapy routinely to patients, the UCSF Cardiology Division has launched a Cardiac Stem Cell Translational Development Program to address these issues. We have numerous on-going projects in the small and large animal heart attack models; in-vitro experiments studying both adult and embryonic stem cell are underway; numerous observational human clinical trials are also currently being performed.


Endocrine

Faculty name: Daniel Bikle, MD

Subspecialty/research focus: Endocrine/hormonal regulation of calcium metabolism in bone and skin.

Title of research project:

Two main areas:

  1. Role of IGF-I and bone development and response to mechanical load.
  2. Role of calcium and vitamin D in regulating keratinocyte differentiation.

Description:

  1. Two main sub projects re IGF-I and bone.
    1. We are exploring the mechanism by which skeletal unloading leads to resistance to the anabolic actions of IGF-I on bone. Data show a clear link to integrin signaling We are pursuing this using both an unloading model (tail suspension) and a loading model (tibial loading, bone cells on flexible substrate).
    2. Using an IGF-I knockout and a conditional (bone specific) IGF-I receptor knockout animal model we are examining the abnormality in bone development in embryos and the resistance to the enabolic effects of PTH on bone postnatally.
  2. Two main sub projects are keratinocyte differentiation.
    1. We are examining the mechanisms by which calcium stimulates keratinocyte differentiation. We have identified key roles for the calcium receptor and for the phospholipase C. We are currently developing epidermal specific knockout models of these two proteins to examine their roles in vivo.

Keratinocytes both produce and respond to the active metabolite of vitamin D, 1,25(OH)2D with changes in keratinocyte differentiation. Our knockout models for the enzyme producing 1.25(OH)2D(1 hydraxylase) and for its receptor (VDR) have abnormalities in the epidermis. The VDR k/o mouse also shows a loss of hair beginning around weaning. We are currently pursing a number of studies investigating the transcriptional activity of VDR, and how this is controlled both in the epidermis and during hair follicle cycling by various co activators and suppressors.


Faculty name: Robert V. Farese, Jr., MD

Contact information: J. David Gladstone Institutes
                                    1650 Owens Street
                                    San Francisco, CA 94158
                                    Tel: 415.734.2000
                                    bfarese@gladstone.ucsf.edu

Subspecialty/research focus: Cellular Lipid and Energy Metabolism

Title/description of research projects: Because energy availability varies, living organisms need to store energy. This is done most efficiently as triacylglycerols (TGs). Within cells, TGs and other nonpolar lipids are stored in cytosolic lipid droplets (LDs). Excessive accumulation of lipids in LDs within tissues underlies the pathogenesis of diseases, such as obesity, diabetes, fatty liver and atherosclerosis. Additionally, lipid storage in LDs is a focus of efforts to increase oil yields from crops or microorganisms. An understanding of how cells synthesize, store and utilize lipids is, therefore, of fundamental importance.

We study the mechanisms of cellular lipid synthesis and storage. Our studies range from the basic biology of diacylglycerol acyltransferases (DGATs) and other enzymes involved in TG synthesis to genetic models aimed at discovering genes that govern LD formation. Our model systems include yeast, mammalian cells, mice and human induced pluripotent stem (iPS) cells. Our discoveries of basic mechanisms from in vitro and cellular studies are tested in whole organisms for their applications to physiology and disease.

Together with Tobias Walther at Yale University, we recently identified a key mechanism involved in LD expansion. We found that growing LDs require specific phospholipids to coat their surfaces and that the synthesis of these lipids is activated at LD surfaces through a fascinating homeostatic mechanism. In recent physiological studies, we showed that mice overexpressing DGAT1 in macrophages, which leads to increased TG storage capacity, are protected against the detrimental consequences of obesity. In collaborative studies with the Ott laboratory, we identified DGAT1 as a host factor that is required for efficient infection of liver cells by the hepatitis C virus and that DGAT1 is required for the virus to induce hepatic steatosis.

Our laboratory also researches the basic mechanisms of frontotemporal dementia (FTD), the most common cause of dementia in people under age 65. As part of the Consortium for FTD Research, we use a variety of model systems to study the pathogenesis of FTD and search for cures. Recent advances include generating murine models of FTD with progranulin deficiency and showing that mice lacking progranulin are predisposed to neuroinflammation, generating and studying iPS cells from FTD patients and establishing yeast models for studying the role of the protein TDP43 in FTD pathogenesis.


Faculty name: Edward Hsiao, MD, PhD

Contact information: Office: 415-476-9732.
                                    Email: Edward.hsiao@ucsf.edu
                                    Website: http://tiny.ucsf.edu/hsiaolab.

Subspecialty/research focus: Endocrinology and MetabolismHuman Genetics
                                                  Skeletal diseases/repair/regeneration
                                                  Metabolic regulation by the skeleton

Title/description of research projects:

Musculoskeletal diseases are the most frequently reported conditions by Americans and the second-greatest cause of disability worldwide. Our research combines a patient-inspired approach with advanced genetic and cell biology methods to understand human skeletal development and disease pathogenesis. Our long term goals are to provide key insights into a wide variety of common, medically-important diseases both in and out of the skeletal system, including osteoporosis, vascular calcification, and bone/cancer interactions, and apply this knowledge to develop new therapeutic avenues for treating human diseases.

We are currently pursuing two main directions:

The role of G-protein coupled receptor hormone signaling in bone and cartilage. We use an “artificial hormone” system to study how one class of hormone signals (G-protein coupled receptors, GPCRs) affects tissue development and function in a variety of bone diseases. We developed one of the first genetic mouse models of fibrous dysplasia of the bone. In addition, we have identified novel GPCRs that are highly expressed in bone but have no previously recognized roles in the skeleton. Additional related projects include studying the roles of GPCRs in fracture repair, the formation of other mineralized tissues such as the teeth, identifying molecular regulators of the GPCR signals in pathologic calcification, and understanding how GPCR signaling in bone-forming cells affect metabolism, bioenergetics, and glucose homeostasis.

Use human iPS cells to understand human skeletal disease pathogenesis.  Current methods for studying bone formation are extremely limited and are often not derived from human tissues. The lack of human specific models leaves a large gap in our ability to understand human skeletal formation. We use human induced pluripotent stem (iPS) cells and tissues created from these iPS cells to study genetic diseases affecting bone and cartilage. These powerful models have helped identify new roles for important GPCR and BMP signaling pathways, and will help identify new treatment strategies for skeletal diseases. Projects will be related to deriving and characterizing a new series of iPS cell lines, generating reporter lines, dissecting the molecular basis of the disease phenotype using single cell analysis, and using exome and whole-genome sequencing to identify genetic interactions.

Short-term and long-term projects are available in all of these areas. Backgrounds in molecular biology, computational biology, genetics, orthopedics, and bioengineering are also welcome!


Faculty name: Jeffrey Milush, PhD

Contact information: SFGH
                                    Bldg 3, Room 609
                                    Ph: 206-4981
                                    Jeffrey.Milush@ucsf.edu

Subspecialty/research focus:

Inflammation; neuronal and endocrine modulation of immune cells; neuroendocrine; glucocorticoid receptor expression and function in immune cells; effect of complementary and alternative medicine on immune function and inflammation; chronic stress; obesity; depression; HIV-1 infection; natural killer cell biology

Title/description of research projects:

My research focuses on two main areas of immunology: (1) the effect of immune activation and inflammation on natural killer (NK) cell phenotype and function; and (2) how the neuroendocrine system controls the development, function, and termination of inflammation and innate and adaptive immune responses. These two areas of interest are united by the hypothesis that persistent inflammation associated with chronic stress (i.e. infectious diseases, psychological stress, chronic inflammatory diseases) disrupts immune cell function, at least in part, through a disruption of neuroendocrine modulation of the immune system. We take a translational approach to this research by studying basic molecular and cellular phenomena, expanding these findings at the level of the experimental animal, and ultimately translating discoveries to patient-oriented research.


Faculty name: Robert Nissenson, PhD

Contact information: VA Medical Center

                                     1700 Owens St., San Francisco

                                    Phone: 415-575-0553
                                    Robert.Nissenson@ucsf.edu

Subspecialty/research focus: Hormonal control of bone and mineral metabolism/ control of bone mass by intracellular signaling in bone cells

Title of research project:

G protein signaling in osteoblasts: These studies focus on the mechanisms underlying the catabolic and anabolic changes in bone that result from specific G protein signals in osteoblasts. Gain of function of specific G protein pathways is achieved by the targeting of Receptors Activated Solely by Synthetic Ligands (RASSLs) to osteoblasts in vivo. Loss of function is produced by induction of G-protein alpha-subunit ablation in vivo. By inducing these changes at different stages of osteoblast differentiation, we are building an integrated model of the role of G protein signaling in controlling skeletal homeostasis.

Interplay between fat and bone: There is a reciprocal relationship between bone marrow adipose tissue and bone mass, but the significance of this for metabolic bone disease is poorly defined.  We hypothesize that bone marrow mesenchymal progenitor cells (MPCs) serve as metabolic sensors, and that metabolic stress promotes an increase in bone marrow adipogenesis at the expense of bone.  We are identifying the signaling pathways and molecular machinery in MPCs that determine the fate of these cells as well as the role of specific adipokines such as adiponectin.


Faculty name: Fred Schaufele, MD

Contact information: freds@diabetes.ucsf.edu
                                    Phone: 415-476-7086

Subspecialty/research focus: Endocrinology/Pituitary; Peripheral Metabolic Tissues; Hormone Synthesis, Action and Drug Discovery.

Title of research project:

Transcription factor interactions at the GH promoter -This project analyzes the subnuclear positions and interactions of factors that regulate the transcription of genes in pituitary cells. Aim 1. compare the effects of mutations in specific Pit-1 and C/EBP activities on transcriptional synergy, release of C/EBP binding to -satellite repetitive DNA, and Pit-1 marshaling of C/EBP to euchromatin, Aim 2. define the effects of the Pit-1 and C/EBP mutants on the biochemical interactions and conformations of C/EBP, Pit-1, and target proteins, Aim 3. determine the effects of Pit-1 and C/EBP expression on GH/PRL promoter binding, -satellite DNA binding, and recruitment of co-factors or modified histones to the promoters and -satellite DNA

Temporal and Spatial Dynamics of Androgen Receptor Conformation and Interactions in Prostate Cancer Cells -This project developed the low throughput FRET technology for following the temporal and spatial changes in the conformation and interactions of the Androgen Receptor following agonist or antagonist addition. Aim 1. Conformation, dimerization, nuclear transport and activity of flutamide-resistant, AR mutants Aim 2. Conformation, dimerization, nuclear transport and activity of AR in different prostate cancer cell environments. Aim 3. AF-2 interaction with FQNLF in the DHT-induced re-positioning of AF-1 towards the LBD.

Novel imaging techniques that compare estrogen receptor structure in tumors and normal tissues of intact living animals -This project uses FRET technology for following in live mouse models, the agonist and antagonist-regulated conformation and interactions of the Estrogen Receptor. Aim 1, Creation of stable cell lines expressing fluorescent protein fusions with ERa Aim 2, FRET imaging in live animal models

High Throughput Identification and Characterization of Novel Anti-Prostate Cancer Therapeutics -This pending pilot project is for the very initial stages in the development of the High Throughput Screen of the Androgen Receptor. -Aim 1: creation of constructs and prostate cancer cell lines for AR high throughput AR imaging -Aim 2: multiplex the AR imaging assay -Aim 3: validate the high throughput AR screening protocol, then conduct an initial screen of a chemical library targeted broadly towards kinases.

High Throughput Identification of Subtype-Selective Breast Cancer Therapeutics -This pending project is for the development of the High Throughput Screen of the Estrogen Receptor. Aim 1: High throughput protocols will be developed on different ER-positive, Luminal A subtype breast cancer cell lines that respond to, or are resistant to, anti-estrogen treatment. Aim 2: These protocols will be used to screen for compounds and compound combinations with highly selective effects on ER biochemistry, on the structure of ER complexes and on breast cell proliferation. Aim 3: Parallel developments in animal imaging will allow monitoring of the efficacy and bioavailability of the lead compounds on the same processes in live animals. Aim 4: The abilities developed in Aims 1-3 will be applied to studies of HER2 in the ERBB2 subtype.


Gastroenterology

Faculty name: D. Montgomery Bissell, MD

Contact information: montgomery.bissell@ucsf.edu
                                   Pager: 443-8983

Subspecialty/research focus: Genetic liver diseases; porphyria

Title/Description of Research Projects: The porphyrias comprise a set of 7 diseases, which are fascinating and, moreover, important to individuals and families who carry a porphyria mutation. Because they are rare, key questions concerning their natural history and optimal management have gone unanswered. Six centers now have linked up formally in a national Porphyria Consortium under the auspices of the NIH Office of Rare Diseases, with funding from NIH/NIDDK. The sites are New York, Galveston, San Francisco, Birmingham, Salt Lake, and Charlotte. Two have labs for biochemical testing and DNA analysis (Galveston and New York, respectively). We are pooling our patients in a database and have enrolled over 400 comprising every type of porphyria, all genetically confirmed. Several clinical studies including treatment trials are under way. Residents involved in the project would learn about the porphyrias, help evaluate patients referred for porphyria (depending on individual schedules) and participate in a clinical research project in which UCSF is the primary site.


Genetics

Faculty name: Edward Hsiao, MD, PhD

Contact information: Office: 415-476-9732
                                    Edward.hsiao@ucsf.edu
                                    Website: http://tiny.ucsf.edu/hsiaolab

Subspecialty/research focus: Endocrinology and Metabolism
                                                  Human Genetics
                                                  Skeletal diseases/repair/regeneration
                                                  Metabolic regulation by the skeleton

Title/description of research projects:

Musculoskeletal diseases are the most frequently reported conditions by Americans and the second-greatest cause of disability worldwide. Our research combines a patient-inspired approach with advanced genetic and cell biology methods to understand human skeletal development and disease pathogenesis. Our long term goals are to provide key insights into a wide variety of common, medically-important diseases both in and out of the skeletal system, including osteoporosis, vascular calcification, and bone/cancer interactions, and apply this knowledge to develop new therapeutic avenues for treating human diseases.

We are currently pursuing two main directions:

The role of G-protein coupled receptor hormone signaling in bone and cartilage. We use an “artificial hormone” system to study how one class of hormone signals (G-protein coupled receptors, GPCRs) affects tissue development and function in a variety of bone diseases. We developed one of the first genetic mouse models of fibrous dysplasia of the bone. In addition, we have identified novel GPCRs that are highly expressed in bone but have no previously recognized roles in the skeleton. Additional related projects include studying the roles of GPCRs in fracture repair, the formation of other mineralized tissues such as the teeth, identifying molecular regulators of the GPCR signals in pathologic calcification, and understanding how GPCR signaling in bone-forming cells affect metabolism, bioenergetics, and glucose homeostasis.

Use human iPS cells to understand human skeletal disease pathogenesis.  Current methods for studying bone formation are extremely limited and are often not derived from human tissues. The lack of human specific models leaves a large gap in our ability to understand human skeletal formation. We use human induced pluripotent stem (iPS) cells and tissues created from these iPS cells to study genetic diseases affecting bone and cartilage. These powerful models have helped identify new roles for important GPCR and BMP signaling pathways, and will help identify new treatment strategies for skeletal diseases. Projects will be related to deriving and characterizing a new series of iPS cell lines, generating reporter lines, dissecting the molecular basis of the disease phenotype using single cell analysis, and using exome and whole-genome sequencing to identify genetic interactions.

Short-term and long-term projects are available in all of these areas. Backgrounds in molecular biology, computational biology, genetics, orthopedics, and bioengineering are also welcome!


Faculty name: John P. Kane, MD, PhD

Contact information: 476-1517

Subspecialty/research focus: Disorders of lipid and carbohydrate metabolism at the gene level; genetic determinants associated with coronary disease and stroke.

Title/description of research project: There is a wide scope of possible studies within the interests being pursued in our laboratory such as the relationship of the genotype of the Lp(a) lipoprotein to disease, investigation of the mechanisms of action of gene polymorphisms recently discovered in our collaborations that are associated with increased risk of MI, etc., the molecular speciation of HDL in relationship to disease phenotypes, effects of medications on the distribution and function of HDL molecular species,etc.,etc.


Faculty name: Robert L. Nussbaum, MD

Contact information: Robert.nussbaum@ucsf.edu
                                   415-476-3200

Subspecialty/research focus: Molecular Genetics
                                                  Hereditary Cancer
                                                  Parkinson Disease

Title/description of research projects:

Role of microbiome and enteric nervous system in Parkinson disease 

Analysis of variants in BRCA1 and BRCA2 genes


Geriatrics

Faculty name: Stephen J. Bonasera, MD, PhD

Contact information: steve.bonasera@ucsf.edu

Subspecialty/research focus: Geriatrics/Neurobiology of Aging basic science

Title of research projects: My laboratory studies how regional gene expression across the CNS (including the hypothalamus, frontal cortex, striatum, and cerebellum) changes with ageing, and the behavioral correlates of these changes. Efforts are specifically focused on studies of age-related dysregulation in gene networks governing microglial-based inflammatory and neuronal-based synaptic responses. Gene expression is quantified using both microarray and qPCR-based methods. We analyze both whole tissue and enriched populations of neurons, microglia, and astrocytes separated by FACS. Mouse home cage behaviors (including eating, drinking, movement, and circadian patterning of activity) are measured with a custom platform that acquires data at a high spatial and temporal resolution. Sophisticated computational approaches are then employed to derive complex behavioral metrics from this home cage data. More traditional approaches to mouse behavioral phenotyping are used as needed. We study how interventions thought to improve cognitive reserve, including exercise and environmental enrichment, alter these inflammatory and synaptic processes. We also apply these methods to better understand the basic biology underlying frailty.


Faculty name: Shweta Choudhry, PhD, MSc

Contact information: Mission Bay Campus
                                    Rock Hall Rm 582A
                                    1550 4th Street
                                    San Francisco, CA 94158
                                    Phone: 415-514-9927
                                    shweta.choudhry@ucsf.edu

Subspecialty/research focus: Genetics of complex disorders including asthma, COPD, interstitial lung disease, cardiovascular disease and type 2 diabetes.

Title of research projects: My research focuses on the population genetics of complex disorders and their related phenotypes in the U.S. understudied populations including Latinos, African Americans and South Asians. We have several ongoing projects that use cutting-edge genetic methods such genome-wide association analysis, admixture mapping and pathway analysis to better understand genetic and environmental risk factors for complex diseases and how interaction between genes and environment can modulate risk for diseases.


Faculty name: John Kane, MD, PhD
                         Professor of Medicine
                         Professor of Biochemistry and Biophysics

Contact information: Phone: 415-476-1517

Subspecialty/research focus: Metabolism of lipids and lipoproteins, genetics of dyslipidemias, genetic determinants of coronary artery disease and stroke

Title of research projects: Molecular properties of human HDL
                                            Genetic determinants of myocardial infarction
                                            Clinical studies of dyslipidemias


Faculty name: Victor Valcour, MD

Contact information: vvalcour@memory.ucsf.edu

Subspecialty/research focus: Geriatric Medicine, HIV

Title/description of research projects:

Dr. Valcour’s research addresses the cognitive consequences of HIV infection through local and international studies in Thailand and Africa. These are all clinical research protocols involving neuropsychological testing, neurological examinations, brain MRIs, and laboratory testing among HIV-infected and HIV-exposed child, adult, and elderly populations. Individuals who work on these projects may learn techniques associated with cognitive characterization of patients and imaging, and clinical care. Opportunities exist to participate in data analysis including imaging analyses and manuscript preparation. For more detailed descriptions of Dr. Valcour’s various research projects, please visit his lab website at :

http://valcourlab.ucsf.edu/mentoring--training.html


Hematology

Faculty Name: Millie Hughes-Fulford, PhD
                         milliehf@aol.com

Subspecialty/research focus:  

Lack of T-cell activation in the absence of Earth gravity: Gravity sensitive signal transduction pathways
Differentiation of monocytes on Earth and in Space: cause of immunosuppression in astronauts
Effect of fatty acids and statin on growth of prostate tumors
Use of stem cells to make a osteopatch for fracture healing

Title of research:

My research interests focus on signal transduction and regulation of cellular growth, including T-cell activation, mechanical stimulation of osteoblasts stem cell differentiation and the growth induction of tumors by essential fatty acids. Our interests focus on the initial signaling events, which trigger a cascade of events leading to cell proliferation/differentiation 24-48 hours later. Although our model systems: T-cells, cancer cells, osteoblasts and monocytes are diverse, the signal pathways and gene expression profiles during early activation share common features.

Mechanisms of T-cell activation and monocyte differentiation in microgravity: This investigation explores the mechanism of action for induction of T-cell IL-2R mRNA units after activation.

Previous experiments by Dr. A. Cogoli have demonstrated that T-cells are not activated in microgravity with the TCR being the most probable site of gravity dependence. Using qRTPCR, Affymetrix gene array, ELISA and Western blots we have discovered the dependence of several signaling pathways on normal Earth gravity during T-cell activation. Our first manuscript is in press in Cellular Signaling (Impact Factor 5.2), the second manuscript is in revision. The re-flight of our STS-107 Leukin experiment will occur in September 2006 on the Russian Soyuz, where we will have the opportunity to verify our ground RPM data in true microgravity (10-3 -10-6 g). The second study, PKINASE flew in October, 2007 investigates how microgravity affects protein kinase C (PKC) signaling in monocytes and the functional consequences of these changes on downstream signaling events, gene expression and cell fate. When protein kinase C isoforms are activated in normal gravity they translocate to the cell membrane, which is a key step in signal transduction by these kinases. Using Affymetrix gene arrays, we will be able to predict which signal pathways are dysfunctional without gravity. These experiments are essential to our understanding the role of gravity in terrestrial life.

Fatty acid regulation of gene and protein expression in cancer: We were the first to show that cox-2 is up regulated in prostate cancer and that it has a feed forward mechanism. The current project focuses on the role of the essential fatty acids induction of mRNA, protein synthesis and proliferation in neoplastic tissues. Using RTPCR, ELISA, signal pathway inhibitors, COX-2 inhibitors and fluorescent microscopy we have demonstrated that the essential fatty acids (EFAs) are involved in early gene expression of inflammatory molecules in tumors. Despite the pronounced differences in the mortality rates of the different cultures, latent prostate cancer found at autopsy occurs at the same frequency in Japanese men as in Caucasian males. These accumulating data suggest that the higher intake of dietary fat in Western society compared to other countries may account for the high rate of prostate cancer incidence in the US with African-Americans having twice the rate of the Caucasian male. Over the past 50 years in the U.S., the ratio of dietary intake of -6 FA vs. -3 FA has increased from 1:2 to 25:1; during this same time frame the incidence of prostate cancer has risen. Even in Japan over the last 30 years, the intake of -6 FA has risen to 4:1 from 2:1 (4). In addition, chemokines have recently been linked to angiogenesis and vascularization. Specifically interleukin 8 (IL-8), interleukin-6 (IL-6) and tumor necrosis factor (TNF) have been linked to angiogenesis, vascularization, tumorogenicity and metastases in prostate cancer in vitro and in vivo both in animals and humans. Since elevated levels of chemokines and cytokines are linked with tumor progression, metastases or survival, we hypothesize that patients eating a Western diet with elevated levels of -6 FAs will have higher levels of chemokine and cytokine synthesis and higher incidence of advanced disease. We have found dramatic increases in chemokines with -6 FA both in vitro and in vivo.

Rapid fracture healing by FGF-2: We are testing if growth factors and their anabolic products selectively induce gene expression needed for effective human mesenchymal stem cell (hMSC) migration, proliferation, and wound healing prior to mineralization both in vitro and in vivo. We will also test the hypothesis that delivering growth factors ex-vivo or in an extracellular matrix (ECM), would drastically lower cost of GF treatment in man and allow faster repopulation of the osteoblasts. Finally we will test the hypothesis that combined therapy using ex-vivo expansion of hMSC by growth factors followed by a differentiation treatment just before transplant will result in better vascularizion, greater bone mass and accelerated mineralization of a fracture. Currently we have identified several ECMs and GFs that facilitate fracture repair.


Faculty name: Yuet Wai Kan, MD, MBBS, DSc

Subspecialty/research focus: Mouse models of sickle cell disease.
                                                  Gene therapy for hematopoietic disease and coronary heart disease

Title of research:

Creation of a mouse model of sickle cell disease:

 We are creating several models of sickle cell anemia that mimic the human haplotypes of sickle cell diseases. These haplotypes result in variable clinical severities due to different fetal hemoglobin expression, and will provide good models for testing therapeutic approaches

Gene therapy for hematopoietic and coronary heart diseases:

We are studying a mouse model of α- thalassemia. As in humans, the homozygous affected fetuses are lethal in the third trimester of pregnancy. We are using several vectors to transducer hematopoietic cells with the human α-globin gene to rescue these mice.

We are devising new AAV vectors that are much more efficient in tranducing liver and hematopoietic cells to study genetic diseases, such as ornithine transcarbamylase deficiency, that are lethal in the newborn.

We are using gene and cell therapy to express VEGF and other angiogenic factors for the treatment of coronary. Contact: Lisa Woldin 415-476-5841


Faculty Name: Charles J. Ryan MD

Contact information: ryanc@medicine.ucsf.edu

Subspecialty/research focus: Oncology, Prostate Cancer
                                                  Hormonal therapies for prostate cancer
                                                  Developmental Therapeutics

Title of research: My research deals with the mechanisms of resistance to standard hormone therapy for prostate cancer patients. As a clinical/translational researcher, I conduct clinical trials of new drugs at the phase I and II level. My major clinical trials target the synthesis of androgens by the adrenal gland. Further, I study the interaction of androgen stimulation and signaling by the Insulin like growth factor (IGF) receptor in prostate cancer models. We do preclinical work in the lab that corresponds to our ongoing clinical trials.


HIV

Faculty Name: Jay A. Levy, MD- Professor of Medicine
                         Department of Medicine
                         Division of Hematology/Oncology
                         513 Parnassus University of California, San Francisco
                         Room S1280
                         San Francisco, CA 94143-1270
                         Tel. (415) 476-4071 Fax. (415) 476-8365
                          jay.levy@ucsf.edu

Subspecialty/research focus: Infectious Diseases
                                                  Immunology
                                                  HIV/AIDS

Description of project: Research interests of our laboratory are directed at understanding the mechanisms of HIV pathogenesis with the hope of designing novel antiviral therapies and an effective AIDS vaccine.

Virus Studies: Biologic, serologic, and molecular characterization of HIV-1 and HIV-2 strains are revealing their extensive heterogeneity and have demonstrated that viruses may evolve differently in the same individual (the immune system, bowel, and the brain). Molecular studies with intraviral recombinants of HIV-1 have shown that very few envelope gene changes can affect tissue tropism, cytopathicity and serum antibody sensitivity. Current anti-HIV experiments are evaluating RNA approaches.

Immune Studies: Recent emphasis in the laboratory has been on anti-HIV innate immune responses. We are evaluating the role of plasmacytoid dendritic cells (PDC), major producers of type 1 interferons. Studies are directed at understanding how HIV-infected cells induce interferon production from PDC and what cell surface molecules, including toll-like receptors, are involved in this process. Another innate response we have defined is the ability of CD8+ lymphocytes to suppress HIV replication without killing the cells. This CD8+ cell noncytotoxic antiviral response (CNAR) is mediated by a novel unidentified CD8+ cell antiviral factor (CAF). CNAR and CAF block HIV transcription. Certain cytokines such as IL-2, IL-15 and IFN-a as well as co-stimulation with CD3 and CD28 antibodies and co-culture with mature dendritic cells can enhance this antiviral response.

The identity of CAF is being determined by protein purification procedures involving mass spectrometry, and molecular analyses, using microarray techniques. Other studies focus on why the CD8+ cell anti-HIV response decreases with time in HIV-infected individuals. In acute HIV infection, we have found that antiviral drugs that reduce HIV plasma loads, decrease the CD8+ cell antiviral response. New treatment directions being evaluated are IL-2 therapy, immunization, and structured treatment interruptions in attempts to restore the host anti-HIV immune response.
Vaccine Studies: Experiments towards deriving an AIDS vaccine involve an HIV-2 DNA vaccine with genetic adjuvants (GM-CSF, B7.2). Immunized baboons are monitored for anti-HIV-2 neutralizing antibodies as well as cell-mediated anti-HIV immune responses. These studies will hopefully pave the way for the development of an effective HIV vaccine for humans.


Faculty name: Victor Valcour, MD

Contact information:  vvalcour@memory.ucsf.edu

Subspecialty/research focus: Geriatric Medicine, HIV

Title/description of research projects:

Dr. Valcour’s research addresses the cognitive consequences of HIV infection through local and international studies in Thailand and Africa. These are all clinical research protocols involving neuropsychological testing, neurological examinations, brain MRIs, and laboratory testing among HIV-infected and HIV-exposed child, adult, and elderly populations. Individuals who work on these projects may learn techniques associated with cognitive characterization of patients and imaging, and clinical care. Opportunities exist to participate in data analysis including imaging analyses and manuscript preparation. For more detailed descriptions of Dr. Valcour’s various research projects, please visit his lab website at :

http://valcourlab.ucsf.edu/mentoring--training.html


Infectious Diseases

Faculty Name: Chip Chambers, MD

Contact information: hchambers@medsfgh.ucsf.edu
                                   phone 415 206 5437

Subspecialty/research focus: infectious diseases, staphylococcal infections, microbial pathogenesis, hospital epidemiology, antimicrobial drug resistance

Title/description of research projects:

I study the pathogenesis and treatment of infections caused by Staphylococcus aureus, in particular the nexus of antimicrobial resistance and virulence, both hallmark traits of this human pathogen. By far the most important resistance is methicillin resistance, i.e., beta-lactam antibiotic class resistance; beta-lactams are the most effective and least toxic of all antibiotics used to treat Staphylococcus aureus infections. A low-affinity penicillin binding protein, PBP 2a, mediates methicillin resistance. (PBPs are integral bacterial membrane proteins that catalyze final steps of cell wall synthesis and they the targets of beta-lactams.) We were the first to report that PBP 2a is inducible by beta-lactams and we described a novel signal transduction pathway that regulates expression of beta-lactamase, and, as it turns out, PBP 2a. Our work demonstrating that antibiotics differ in affinity for PBP 2a and as a result their antibacterial activity provided a foundation for drug discovery efforts in the pharmaceutical industry to identify compounds with high affinity for PBP 2a. Several such compounds have been developed and two cephalosporins are in late stage clinical development. We are interested in understanding mechanisms of resistance to high binding affinity beta-lactams and have identified mutations in PBP 2a and, unexpectedly, in other genes that confer high-level resistance to the compounds. We continue to pursue this area of research.

A little over a decade ago we and others recognized a change in the epidemiology of methicillin resistant S. aureus (MRSA) strains. MRSA, almost exclusively a hospital organism, was being isolated from patients who had no contact with the healthcare system. Through our work and the work of others it became apparent that these community strains of MRSA were distinct from those circulating in hospitals. By 2004 one particular clone known as USA300, originally identified by Dr. Perdreau-Remington at San Francisco General Hospital, accounted for the vast majority of community MRSA isolates in the United States. We have contributed to defining the clinical and molecular epidemiology of what is now an epidemic of community MRSA. In addition to their epidemicity USA300 strains are quite virulent and capable of causing rapidly lethal infections. We have characterized a novel mobile genetic element, ACME, which is unique to USA300 and appears to encoded one or more virulence determinants. We have also developed a rabbit pneumonia model that has allowed us to elucidate mechanisms by which Panton-Valentine leukocidin (PVL), a staphylococcal leukotoxin strongly associated with USA300 and other community MRSA strains, produces such extensive tissue damage. Our research to better understand the basis of this convergence of resistance and virulence is on going. Emergence of community MRSA has profound implication for therapy, as beta-lactams can no longer be relied upon for empirical therapy. We are involved in preclinical and clinical evaluation of several investigational agents for treatment of MRSA infections. In addition my research group is overseeing a multicenter clinical trial of the efficacy of oral, generic antibiotics for treatment of skin and soft tissue infections caused by MRSA.


Faculty name: Maggie Feeney, MD

Contact information: Margaret E. Feeney MD MSc
                                    Associate Professor
                                    University of California, San Francisco
                                    Division of Experimental Medicine
                                    1001 Potrero Avenue
                                    Building 3, Room 525a
                                    San Francisco CA 94110
                                    Office (415) 206-8218
                                    Fax (415) 206-8091
                                    Margaret.feeney@ucsf.edu

Subspecialty/research focus: Infectious Diseases & Immunology
                                                  Human Immune Response to Malaria

Title/description of research projects:

The broad goals of my research program are to identify correlates of protective immunity to HIV and malaria in order to guide the rational design of vaccines and immunomodulatory therapies. We are also interested in understanding how the immune response of infants and young children differs from that of adults, in order to optimize the immunogenicity of vaccines and other strategies targeting infants. Current projects include:
1) Identifying in vitro correlates of protective immunity to malaria in African children
2) Determining the impact of malaria chemoprevention on the development of immunity to pre-erythrocytic and erythrocytic stage malaria antigens
3) Understanding age-related differences in the immune response to pathogens such as HIV and malaria
4) Determining the impact of in utero exposure to malaria antigens on fetal tolerance and the subsequent immune response to childhood malaria


Faculty name: Lynda Frassetto, MD

Contact information: phone 476-6143
                                    frassett@gcrc.ucsf.edu

Subspecialty/research focus: Clinical research on the pharmacology of medication interactions (believed to be due to membrane uptake or efflux transporters and intracellular metabolizing enzymes) Clinical research on electrolyte and acid/base changes with diet and exercise

Title/description of research projects: Medication interaction studies -- ongoing studies, have been working for the last 6 years with the HIV-transplant group, and new studies on effects of orange juice on lasix absorption and action, and glyburide activity when given with ciprofloxacin or rifampin to be started in spring 2006

Diet and exercise - presently starting the "Paleo diet" study -- to see if eating a "Stone Age" diet (high in potassium, fiber, antioxidants, base-producing anions) will improve the ability to exercise or recover from exercise, vascular reactivity, and lipid/glucose profiles. Will soon be starting a study on salt intake and changes in acid/base status.

 


Faculty name: Oren Rosenberg, MD/PhD

Contact information: phone 415-514-0412
                                    oren.rosenberg@ucsf.edu

Subspecialty/research focus: Basic research into the pathogenesis of Mycobacterium tuberculosis, the causative agent of tuberculosis.  We use modern molecular techniques to study an ancient disease. 

Title/description of research projects: We study the structure and function of bacterial pathogenesis using a multidisciplinary approach that includes structural biology, biophysics and bacterial genetics. Our goal is to understand and manipulate virulence systems in bacteria so as to find and exploit vulnerabilities. Ultimately, we hope to contribute to the discovery of more effective, safer, and cheaper treatments for infectious diseases.

Projects in the lab would vary with experience. Please visit rosenberg.ucsf.edu for more information.


Nephrology

Faculty name: David Pearce, MD
                         Professor of Medicine and
                         Cellular & Molecular Pharmacology

Contact information: Genentech Hall Room N272C
                                    University of California, San Francisco 94158
                                    david.pearce@ucsf.edu
                                    Phone: 415-476-7015

Subspecialty/research focus: Nephrology

We are interested in basic signaling mechanisms that control renal ion transport and metabolism. Clinically, this work is related to the pathogenesis of hypertension and type 2 diabetes. Importantly, these two diseases are frequently linked, and our work aims to characterize the underlying mechanisms.

Title/Description of Research Projects:

1. The role of SGK1 as a signal integrator in kidney metabolism and blood pressure control: why do diabetes and hypertension track together?

2. Aldosterone action in renal and non-renal tissues: why does this essential hormone cause cardiovascular damage in the context of the modern world.


Faculty name: Alan S Verkman, MD, PhD

Subspecialty/research focus: Nephrology; water and ion transport mechanisms, in kidney, brain, eye, lung, and GI tract; small molecule drug discovery; mouse models of membrane transporter disease (cystic fibrosis, nephrogenic diabetes insipidus) for testing new therapies.

Title of research project: Small molecule therapies of membrane transporter diseases.
Brief Description: Projects available depending on research interests. See www.ucsf.edu/verklab. Projects include identification and testing of small molecule therapies for membrane transporter diseases; phenotype analysis of transgenic mouse models.


Oncology

Faculty name: Trever Bivona MD, PhD

Contact information: tbivona@medicine.ucsf.edu

Subspecialty/research focus: Medical Oncology/ Tumor biology and genetics and targeted cancer therapy

Title/description of research projects:

I am a laboratory-based physician-scientist with a Ph.D. in cell and molecular biology and a board certified medical oncologist. Clinical experiences inspire my laboratory investigations and provide opportunities to translate scientific discoveries aimed at improving the personalized treatment of cancer patients. The goal of my research program is to define the molecular pathogenesis of human cancers through both basic and translational studies with a particular focus on lung cancer, the leading cause of cancer mortality in the world. Our aim is to discover and molecularly characterize tumor-cell specific vulnerabilities that can be therapeutically exploited as novel treatment strategies to improve the survival of patients with lung, and potentially, other cancers. To accomplish our goals, we have a developed an integrated approach to define the molecular mechanisms by which oncogenes drive the growth of human lung cancers and by which tumors evade oncogene-targeted treatments. Our approach leverages state-of-the-art functional genomics RNA interference screening methodologies, highly relevant preclinical models of lung cancer that accurately represent human lung cancer, and prospectively acquired human lung cancer specimens and clinical data. Using this approach we recently identified several novel mechanisms of resistance to EGFR (epidermal growth factor receptor) inhibitors in lung cancers with activating (oncogenic) mutations in EGFR. Our work has defined new rational companion therapeutic targets that when inhibited may enhance responses to EGFR inhibitors in lung cancer patients. Importantly, we are uniquely positioned to translate our findings into patients through validation studies in human cancer specimens and future mechanism-based, hypothesis-driven clinical trials in cancer patients. The overall goal is to more fully define the molecular architecture governing tumor initiation and progression and to translate this knowledge into clinical applications that improve the survival of patients.


Faculty name: Yun-Fai Chris Lau, PhD

Contact information: Division of Cell and Developmental Genetics
                                    Department of Medicine
                                    Veterans Affairs Medical Center, 111C5
                                    University of California, San Francisco
                                    4150 Clement Street
                                    San Francisco, CA 94121
                                    (415) 379-5526 (Office) (415) 221-4810 x3434 (Laboratory)
                                    (415) 750-6633 (FAX)
                                    chris.lau@ucsf.edu

Subspecialty/research focus: Molecular genetics, Y chromosome genes, sex determination mechanism, pathogenesis of testicular germ cell tumors and prostate cancer, cancer stem cells, sexual dimorphism in human diseases.

Title/description of research project:

The Y chromosome is a man-only and the smallest chromosome of the human genome. The Y-genes are involved in male sex differentiation; spermatogenesis and various less understood sexual dimorphisms (such as in brain development). Dysfunctions of Y-specific genes, under certain conditions, lead to oncogenesis, such as the testis and prostate cancers, and sex-biased disease phenotypes, such as autism spectrum disorder (with a manifestation ratio of 4:1 between boys and girls). Our research focuses on two aspects of these processes, i.e. sex determination and oncogenesis. We use advanced technologies, including molecular genetics, proteomics, genomics, microarray analysis, bioinformatics, chromatin biochemistry and transgenic mouse strategies, to study 1) how the testis differentiation is switched on during embryogenesis, and 2) when dysregulated, how the Y chromosome genes contribute to male-specific cancers.

Recent exploratory projects include 1) evaluation of cell penetrating peptides as therapeutics in neurodegeneration and cancers; and 2) epigenetic effects of Y chromosome genes in sex-biased diseases, such as autism and Hirschsprungs disease.


Faculty name: James L. Rubenstein, MD, PhD

Contact information: UCSF Hematology/Oncology
                                    Health Sciences East 1260
                                    505 Parnassus Avenue
                                    415-502-4430

Subspecialty/research focus: Hematology/Oncology
                                                  Brain Tumors
                                                  Lymphoma
                                                  Immunotherapy
                                                  Diagnostic Biomarkers
                                                  Neuroimaging
                                                  Myeloid Cell Biology

Title/description of research projects:

1) Molecular Pathogenesis of primary CNS Non-Hodgkin s Lymphoma (PCNSL) Mechanisms of CNS Metastasis and Invasion and Development of Novel Therapies.

Using novel primary and secondary CNS lymphoma cell lines which my laboratory has developed, we are evaluating and dissecting molecular regulators of CNS metastasis and brain invasion as well as evaluating candidate mediators of drug resistance.  We are performing preclinical analysis to determine the potential utility of disruption of survival signals mediated by PI3 kinase, JAK/STAT, and SDF-1/CXCR4 an survival pathways in CNS lymphoma.  We are also investigating the potential utility of disruption of the cereblon pathway via the IMiD, lenalidomide.   These studies are being conducted in collaboration with a variety of pharmaceutical companies including Incyte, Novartis, Celgene, Abbott and Genzyme.  The aim of these investigations is to identify candidate preclinical agents and combinations which have activity in refractory disease and to apply this information to the development of new phase I trials for patients with recurrent disease.  An example of this success of this approach is our recent demonstration of the preclinical utility of lenalidomide in an orthotopic xenograft models of CNS lymphoma using patient-derived tumor.  We are using this approach to identify biomarkers which may predict lenalidomide resistance as well as novel strategies to overcome lenalidomide resistance.  In addition, we are applying MRI-metabolic imaging approaches to detect CNS lymphoma invasion and to evaluate therapeutic response.  The successful development of these studies and methods may shed light on mechanisms of CNS metastasis as well as have significant application in the clinic.  

2) Macrophage Polarization as a Biomarker of Prognosis and Mediator of Drug Resistance in CNS Lymphoma and Myeloma.  We are using a novel flow-cytometry-based method which my lab developed to isolate and quantify and transcriptionally define subpopulations of activated macrophages from the CSF and blood of CNS lymphoma and myeloma patients. In particular, we are able to isolate human macrophages bearing features of classical or M1 activation as well as macrophages bearing features of alternative or M2 activation. We are testing the hypothesis that IL-4 induced M2 polarization contributes to acquired rituximab resistance. Thus far our data provides evidence for distinct patterns of Fc receptor expression among the distinct macrophage subpopulations, consistent with the effects of IL-4 receptor signaling. These studies, in collaboration with Dr. Clifford Lowell, likely represent the first genomic analysis of distinct subpopulations of tumor macrophages isolated from patients.   Serial analysis of activated macrophage populations in the clinical setting demonstrates that the M2:M1 ratio is an adverse prognostic biomarker in CNS lymphoma and in systemic multiple myeloma.

3) Identification of CSF biomarkers of primary and secondary CNS lymphoma.Establishing the diagnosis of primary and secondary CNS involvement of non-Hodgkin's lymphoma is often difficult; cytological testing of the CSF is highly insensitive and not all lesions are amenable to brain biopsy. For this reason, diagnostic delays are common and are associated with adverse outcome. For the past seven years our lab has pursued the hypothesis that the CNS dissemination of lymphoma results in the elaboration of specific molecular signals in CSF that could be used as biomarkers for diagnosis as well as prognosis of these conditions. We have now established an in-depth proteomic database of CSF peptides which are differentially expressed in the CSF in the setting of CNS lymphoma. In addition, we have used immunologic techniques to validate these findings and to demonstrate the potential of biomarkers to enhance the diagnostic armamentarium in the evaluation of focal brain lesions and in the screening of patients at risk for secondary CNS lymphoma.  We have recently conducted a multicenter, international study of CSF biomarkers in CNS lymphoma and have validated a biomarker pair with 99% specificity for CNS involvement.  We have developed a molecular test based upon CSF protein biomarkers which has great clinical utility to non-invasively diagnose CNS lymphoma lesions in patients in whom brain biopsy is not a favored option.  A manuscript describing these findings was recently published in Blood.


Faculty name: Charles J. Ryan MD

Contact information: ryanc@medicine.ucsf.edu

Subspecialty/research focus: Oncology, Prostate Cancer
                                                  Hormonal therapies for prostate cancer
                                                  Developmental Therapeutics

Title of research: My research deals with the mechanisms of resistance to standard hormone therapy for prostate cancer patients. As a clinical/translational researcher, I conduct clinical trials of new drugs at the phase I and II level. My major clinical trials target the synthesis of androgens by the adrenal gland. Further, I study the interaction of androgen stimulation and signaling by the Insulin like growth factor (IGF) receptor in prostate cancer models. We do preclinical work in the lab that corresponds to our ongoing clinical trials.


Faculty name: Fred Schaufele, MD  

Contact information: freds@diabetes.ucsf.edu
                                   Phone: (415) 476 7086

Subspecialty/research focus: Endocrinology/Pituitary; Peripheral Metabolic Tissues; Hormone Synthesis, Action and Drug Discovery.

Brief description: Transcription factor interactions at the GH promoter -This project analyzes the subnuclear positions and interactions of factors that regulate the transcription of genes in pituitary cells. Aim 1. compare the effects of mutations in specific Pit-1 and C/EBP activities on transcriptional synergy, release of C/EBP binding to -satellite repetitive DNA, and Pit-1 marshaling of C/EBP to euchromatin, Aim 2. define the effects of the Pit-1 and C/EBP mutants on the biochemical interactions and conformations of C/EBP, Pit-1, and target proteins, Aim 3. determine the effects of Pit-1 and C/EBP expression on GH/PRL promoter binding, -satellite DNA binding, and recruitment of co-factors or modified histones to the promoters and -satellite DNA.

Temporal and Spatial Dynamics of Androgen Receptor Conformation and Interactions in Prostate Cancer Cells -This project developed the low throughput FRET technology for following the temporal and spatial changes in the conformation and interactions of the Androgen Receptor following agonist or antagonist addition. Aim 1. Conformation, dimerization, nuclear transport and activity of flutamide-resistant, AR mutants Aim 2. Conformation, dimerization, nuclear transport and activity of AR in different prostate cancer cell environments. Aim 3. AF-2 interaction with FQNLF in the DHT-induced re-positioning of AF-1 towards the LBD.

Novel imaging techniques that compare estrogen receptor structure in tumors and normal tissues of intact living animals -This project uses FRET technology for following in live mouse models, the agonist and antagonist-regulated conformation and interactions of the Estrogen Receptor. Aim 1, Creation of stable cell lines expressing fluorescent protein fusions with ERa Aim 2, FRET imaging in live animal models.

High Throughput Identification and Characterization of Novel Anti-Prostate Cancer Therapeutics -This pending pilot project is for the very initial stages in the development of the High Throughput Screen of the Androgen Receptor. -Aim 1: creation of constructs and prostate cancer cell lines for AR high throughput AR imaging -Aim 2: multiplex the AR imaging assay -Aim 3: validate the high throughput AR screening protocol, then conduct an initial screen of a chemical library targeted broadly towards kinases.

High Throughput Identification of Subtype-Selective Breast Cancer Therapeutics -This pending project is for the development of the High Throughput Screen of the Estrogen Receptor. Aim 1: High throughput protocols will be developed on different ER-positive, Luminal A subtype breast cancer cell lines that respond to, or are resistant to, anti-estrogen treatment. Aim 2: These protocols will be used to screen for compounds and compound combinations with highly selective effects on ER biochemistry, on the structure of ER complexes and on breast cell proliferation. Aim 3: Parallel developments in animal imaging will allow monitoring of the efficacy and bioavailability of the lead compounds on the same processes in live animals. Aim 4: The abilities developed in Aims 1-3 will be applied to studies of HER2 in the ERBB2 subtype.


Faculty name: Darya Soto, MD

Subspecialty/research focus: Lung Cancer, Angiogenisis

Title of research project: The Tumor Microenvironment in Mice with Lung Adenocarcinoma.
Brief Description: We use a mouse model of lung adenocarcinoma to study the tumor microenvironment. These studies include understanding the inflammatory cells that may promote malignant progression directly or indirectly by influencing the tumor andiogenic vasculature. The inflammatory cells we focus on are mast cells, neutrophils and macrophages, We also study specific angiogenic proteins expressed by both the vasculature and bye the inflammatory cells in the tumor stroma. The long-term goal of our project is to design specific antitumor therapies.


Orthopedics

Faculty name: Edward Hsiao, MD, PhD

Contact information: Office: 415-476-9732.
                                    Edward.hsiao@ucsf.edu
                                    Website: http://tiny.ucsf.edu/hsiaolab

Subspecialty/research focus: Endocrinology and Metabolism
                                                  Human Genetics
                                                  Skeletal diseases/repair/regeneration
                                                  Metabolic regulation by the skeleton

Title/description of research projects:

Musculoskeletal diseases are the most frequently reported conditions by Americans and the second-greatest cause of disability worldwide. Our research combines a patient-inspired approach with advanced genetic and cell biology methods to understand human skeletal development and disease pathogenesis. Our long term goals are to provide key insights into a wide variety of common, medically-important diseases both in and out of the skeletal system, including osteoporosis, vascular calcification, and bone/cancer interactions, and apply this knowledge to develop new therapeutic avenues for treating human diseases.

We are currently pursuing two main directions:

The role of G-protein coupled receptor hormone signaling in bone and cartilage. We use an “artificial hormone” system to study how one class of hormone signals (G-protein coupled receptors, GPCRs) affects tissue development and function in a variety of bone diseases. We developed one of the first genetic mouse models of fibrous dysplasia of the bone. In addition, we have identified novel GPCRs that are highly expressed in bone but have no previously recognized roles in the skeleton. Additional related projects include studying the roles of GPCRs in fracture repair, the formation of other mineralized tissues such as the teeth, identifying molecular regulators of the GPCR signals in pathologic calcification, and understanding how GPCR signaling in bone-forming cells affect metabolism, bioenergetics, and glucose homeostasis.

Use human iPS cells to understand human skeletal disease pathogenesis.  Current methods for studying bone formation are extremely limited and are often not derived from human tissues. The lack of human specific models leaves a large gap in our ability to understand human skeletal formation. We use human induced pluripotent stem (iPS) cells and tissues created from these iPS cells to study genetic diseases affecting bone and cartilage. These powerful models have helped identify new roles for important GPCR and BMP signaling pathways, and will help identify new treatment strategies for skeletal diseases. Projects will be related to deriving and characterizing a new series of iPS cell lines, generating reporter lines, dissecting the molecular basis of the disease phenotype using single cell analysis, and using exome and whole-genome sequencing to identify genetic interactions.

Short-term and long-term projects are available in all of these areas. Backgrounds in molecular biology, computational biology, genetics, orthopedics, and bioengineering are also welcome!


Pharmacology

Faculty name: Lynda Frassetto, MD

Contact information: Office476-6143
                                    frassett@gcrc.ucsf.edu

Subspecialty/research focus:  Nutrition and acid-base physiology, transplantation in HIV-infected subjects

Title/description of research projects:

A series of studies on the influence of "Paleolithic-type" diets on lipid and glucose metabolism in healthy subjects and those who are insulin resistant - one project in type 2 diabetics, another in women with PCOS.

Exercise and vascular physiology in healthy sedentary controls and athletes as part of an ongoing trial of renal and liver transplantation in HIV-infected subjects.

Pharmacokinetics of antiretrovirals and immunosuppressant interactions.

Adverse effects of disease and medications on body composition and bone, and the cardiovascular system.


Pulmonary

Faculty name: Kamran Atabai, MD

Contact information: Kamran.Atabai@UCSF.edu

Subspecialty/research focus: Pulmonary disease.
                                                  Metabolic disease/diabetes/obesity

Title/description of research projects:

The main focus of my laboratory is examining the role of the extracellular matrix, in particular the integrin ligand Mfge8, in regulating inflammation, tissue remodeling, and vascular function as these processes relate to cardiovascular disease. We have several different areas of investigation that have been generated from studies related to this primary focus. (1) We have been examining the role of cell-mediated collagen turnover in regulating the severity of tissue fibrosis using both mouse models of fibrosis and RNAi based whole genome screen of collagen turnover in Drosophila phagocytes. (2) We have been examining the role of Mfge8 in regulating inflammation and proliferation in both airway and vascular smooth muscle. In airway smooth muscle, we have been exploring a pathway by which Mfge8 prevents cytokine-induced increases in calcium sensitivity thereby preventing airway obstruction in models of allergic airway disease. In vascular smooth muscle, we have been focused on understanding the mechanisms by which Mfge8 promotes neointimal hyperplasia and how these effects regulate vascular disease such as vascular stenosis post percutaneous angioplasty and bypass grafting and pulmonary hypertension. (3) We have been investigating the role of Mfge8 in coordinating fatty acid uptake and promoting development of obesity and insulin resistance. We are focused on understanding the exact molecular mechanisms of this pathway with the goal of potentially targeting it for therapeutics aimed at limiting the development of insulin resistance and obesity.


Faculty name: Hal Chapman, MD

Contact information: hal.chapman@ucsf.edu

Subspecialty/research focus: Pulmonary and Critical Care
                                                  Role of lung stem cells in tissue regeneration after acute/chronic lung injury

Title/description of research projects:

1. Assist a team defining surface markers of human epithelial stem/progenitor cells in the lung parenchyma as tools to identify and quantify these cells during lung disease, especially interstitial lung disease. This project involves learning flow cytometry and the basics of tissue processing and immunostaining.

2. Establish a model of lung cancer initiation in mice specific to recently described
lung stem cells to ask the question of whether early invasiveness in lung cancer is a function of the cell of origin. This project uses already available genetically modified mice and will require handling/processing mice and immunohistochemistry.

3. Review a panel of lung biopsy specimens from patients with interstitial lung disease to determine whether there is a correlation between immunohistochemical evidence of regenerative activity and clinical profiles.


Faculty name: James A. Frank, MD

Contact information: UCSF
                                    Pulmonary and Critical Care Medicine
                                    SFVAMC, Box 111D, Building 203, Room 3A53
                                    221-4810 x4137 or x4269
                                    james.frank@ucsf.edu

Subspecialty/research focus: Pulmonary & Critical Care, acute lung injury, lung development, repair and fibrosis, lung cancer

Title/description of research projects: 
Translational, laboratory-based research projects focused on the electrophysiological properties of the paracellular pathway in epithelia, transcriptional regulation of tight junction constituents, cell signaling, and protein trafficking in cells, tissues, and clinical specimens.

Regulation of alveolar barrier function by claudins
Alveolar barrier repair following injury
Role of junctional proteins in epithelial cell migration


Faculty name: Laurence Huang, MD
                         Professor of Medicine
                         Chief, AIDS Chest Clinic
                         San Francisco General Hospital
                         Mailing address:
                         Positive Health Program, Ward 84
                         San Francisco General Hospital
                         995 Potrero Avenue
                         San Francisco, CA 94110
                         Telephone: (415) 476-4082 extension 406
                         Fax: (415) 476-6953
                         Lhuang@php.ucsf.edu

Subspecialty/research focus: HIV- Associated Pulmonary Disease, Pneumocystis Pneumonia (PCP)

Title of research project: Molecular Epidemiology Studies of Pneumocystis Pneumonia

Description of project: Dr. Huang's main clinical and clinical research interests are in HIV-associated pulmonary disease and especially Pneumocystis pneumonia (PCP). He has collaborations with researchers at the National Institutes of Health, the University of Cincinnati, Makerere University (in Kampala, Uganda), the University of Pittsburgh, and Yale University as well as independent studies on PCP and ICU outcomes among HIV-infected patients. Current research studies include:

Development and validation of several new molecular applications to PCP, including the use of a quantitative PCR assay on oropharyngeal wash specimens to diagnose PCP and development of Pneumocystis antibody assays to study Pneumocystis epidemiology and transmission.

Comprehensive molecular-epidemiology study to address the question of whether PCP in humans results from person-to-person transmission (as has been convincingly demonstrated from animal-to-animal laboratory studies) and whether disease results from reactivation of latent infection or from recent exposure and infection.

Prospective cohort study of the incidences, persistence, and consequences of Pneumocystis colonization both for the individual under study as well as for the potential as a reservoir for the organism.

Prospective cohort study of the incidence and persistence of Pneumocystis colonization among health care workers (HCW).

Creation of an international clinical research network to study HIV-associated pulmonary diseases worldwide.


Faculty name: Mark R. Looney, MD

Contact information: 513 Parnassus Avenue
                                    HSE 1355A
                                    San Francisco, CA 94143-0130
                                    mark.looney@ucsf.edu
                                    Phone: 476-9563

Subspecialty/research focus: Pulmonary and Critical Care
                                                  Acute lung injury
                                                  Platelet biology
                                                  Lung transplantation

Title/description of research projects:

My laboratory conducts basic and translational research on acute lung injury using clinically-relevant animal models that we use to investigate the innate immune response, including the role of platelets, neutrophils, and neutrophil extracellular traps. We have developed intravital imaging techniques to direct visualize the mouse lung and track immune events during homeostatic and injury conditions. We also have active projects on lung transplantation using a mouse, orthotopic lung transplant model and human biospecimens. Motivated residents are welcomed to participate in any of these projects.


Faculty name: Michael A. Matthay, MD

Subspecialty/research focus: Pulmonary/Critical Care

Title of research project: Clinical and also lab based studies of acute lung injury.

Description of project: Studies of biological markers in plasma and edema fluid of patients with acute lung injury or more basic lab.


Faculty Name: Jay Nadel, MD

Contact information: UCSF School of Medicine
                                    513 Parnassus Avenue, Room S1183
                                    San Francisco, CA 94143-0130
                                    Phone:415-476-1105
                                    Fax: 415-476-8391
                                    jay.nadel@ucsf.edu

Subspecialty/research focus: Pulmonary and Critical Care/
                                                  My laboratory research focuses on airways, but various epithelia (eg., including gastrointestinal) are included.

Title/description of research projects:

"Invaders" from the environment (eg, viruses, bacteria, cigarette smoke, allergens, occupational irritants) invade the host after deposition on the airway epithelial surface. The epithelium responds to these invaders by intercepting the signals and developing a series of defensive responses that include leukocyte mobilization, the production of antibacterial peptides, mucin production (to aid in trapping and clearing of foreign particulates). These so-called innate immune responses also include healing of wounded epithelium via epithelial proliferation and production of new blood vessels (angiogenesis). Normally, these host responses prevent invasion with few symptoms. However, occasionally overexuberant inflammatory responses occur, leading to chronic inflammatory diseases [eg, asthma, chronic obstructive pulmonary diseases (COPD), cystic fibrosis] or overexuberant proliferative responses (cancer). Over the past several years, my laboratory has discovered a series of signaling pathways responsible for multiple epithelial defensive responses. We have developed therapies for blocking the exuberant responses, which we believe to be important in the pathogenesis of chronic airway diseases.



Faculty name: Anthony Shum, MD

Contact information: email: anthony.shum@ucsf.edu,

                                    website: http://shumlab.ucsf.edu/index.html

Subspecialty/research focus: Pulmonary disease, autoimmunity, immune tolerance, ER stress, translational research, interstitial lung disease, whole exome sequencing

Title/description of research projects: The Shum lab seeks to understand the pathogenesis of autoimmune-associated lung disorders through translational approaches in mouse and human studies.  The major goals of the lab include 1) uncovering genetic underpinnings of autoimmune-associated lung disease using next generation sequencing 2) defining the specificity of the immune response in patients with lung autoreactivity 3) defining immune effector mechanisms of lung autoreactivity in animal models.

Role of intracellular trafficking in the generation of autoimmunity: ER stress is increasingly recognized as an important mechanism in the pathogenesis of both autoimmunity and interstitial lung disease. We are studying a unique set of families with a rare Mendelian form of autoimmunity characterized by interstitial lung disease and arthritis. In collaboration with investigators at Baylor College of Medicine, we performed whole exome sequencing to identify four distinct missense mutations each of which are predicted to cripple the same functional domain of a protein involved in retrograde Golgi-ER transport. Using patient cell lines and tools developed in the lab, a major focus of our group seeks to understand the molecular mechanisms by which defective Golgi-ER transport leads to autoimmunity.

Loss of tolerance to lung self-antigens in the generation of autoimmune-associated ILD: We recently discovered novel mouse and human lung antigens (BPIFB1) targeted in autoimmune-mediated ILD through work in the Aire translational model of human autoimmune polyglandular syndrome Type 1 (APS1). Lung autoimmunity in our model is linked to a well-defined breakdown in immune tolerance, as defects in Aire lead to known defects in central tolerance, and more importantly, shows relevance to more common forms of autoimmune-associated ILD. Strikingly, a subset of non-APS1 patients with autoimmune ILD harbor autoantibodies to BPIFB1, the major human antigen we identified in our model. These results strongly suggest that the Aire model is an ideal system for understanding the role of lung-specific autoimmunity in the pathogenesis of ILD. Using Aire-deficient mice, we are investigating the role of Th27 cells in autoimmune lung fibrosis and defining the role of BPIFB1 as a major autoantigen in lung autoimmunity. Other ongoing projects include the development of clinical tools for improved diagnosis and disease monitoring of autoimmune-associated ILD in patients.

The lung as a site of initiation for rheumatoid arthritis: Rheumatoid arthritis (RA) is the most common inflammatory arthritis affecting nearly 0.5-1% of individuals worldwide. RA is a complex disease with multiple environmental and genetic risk factors. A gene-environment interaction between cigarette smoking and the HLA shared epitope (SE) alleles has been well-described. Case-control studies demonstrate that patients who have 2 HLA SE genes, smoke cigarettes and harbor anti-citrullinated protein antibodies (ACPA) have a 20 fold increase for the development of RA compared to nonsmokers carrying no SE alleles. This suggests that bronchiolar inflammation from smoking may lead to citrullination of proteins in the lung that precipitates RA in genetically susceptible patients. Using whole exome sequencing in a family with a rare form of autosomal dominant RA and ILD, we have identified molecular targets that may link defects in the lung with the development of RA. Using a combination of mouse models, patient cell lines, and stably expressing cell lines expressing the mutant protein, we are investigating the role of the lung epithelium in the initiation of lung citrullination and the onset of systemic RA disease.



Contact information: Prescott G. Woodruff, MD, MPH
                                    Assistant Professor of Medicine
                                    Phone: 415-514-2061
                                    Fax: 415-476-0752
                                    Prescott. woodruff@ucsf.edu
                                    Webpage: http://woodrufflab.ucsf.edu/

Subspecialty/research focus:

Pulmonary Medicine - Our research comprises a program of NIH-funded clinical and translational research into a range of lung diseases including asthma, chronic obstructive pulmonary disease (COPD), and granulomatous lung diseases (e.g. sarcoidosis and hypersensitivity pneumonitis). These studies fall into three specific categories: 1) the identification of distinct molecular sub-phenotypes of these diseases, 2) the elucidation of disease-relevant mechanisms of airway inflammation and remodeling in the lung and 3) clinical trials of novel therapeutic approaches

Title of research project/description of project: The identification of molecular sub-phenotypes of asthma and COPD:

These studies are funded by:

An R01 from the NIH/NHLBI, entitled "Molecular Phenotyping of Asthma" (R01 HL-095372) which has applied genomic analyses to airway samples from patients with asthma to distinguish Th2-driven and non-Th2-driven sub-phenotypes of asthma that have distinct clinical, pathological and treatment-related characteristics.

A seven-year NIH contract to apply similar methods to study COPD as part of the NHLBI Spiromics Project (N01 HR-08-08). The goal of the Spiromics project is to identify molecular phenotypes of COPD and to develop intermediate outcome measures for clinical trials.

Mechanisms of airway inflammation and remodeling in lung diseases:

These studies apply innovative methods for quantitative morphometry and gene expression analyses to human tissue samples obtained at fiberoptic bronchoscopy. In work to date, we have applied these methods to study mechanisms of disease in asthma, COPD and sarcoidosis. Ongoing work in this area is supported by the NIH (R01 HL-095372). Our approaches combine the application of gene expression profiling methods (microarrays, qPCR, laser capture microdissection) and design-based stereology (for quantitative measurement of tissue remodeling in human samples).

Sample analysis and support for Clinical Trials:

Finally, the Woodruff Laboratory supports sample analyses for clinical trials in asthma and COPD in both NIH and industry-supported studies. These sample analyses include measurement of changes in airway remodeling in response to specific therapeutic interventions, assessment of inflammation and the application of biomarkers to enhance the interpretation of clinical trials.


Faculty name: Prescott G. Woodruff, MD, MPH

Contact information: Phone (415) 514-2061
                                    UCSF Address: Box 0111, Moffitt Hospital Rm M1098
                                    prescott.woodruff@ucsf.edu
                                    Webpage: http://pulmonary.ucsf.edu/faculty/woodruff.html

Subspecialty/research focus: Pulmonary Medicine
                                                  Asthma
                                                  COPD

Title/description of research projects:

My research activity encompasses both clinical and bench research into the mechanisms of diseases of the airways and, consequently, much of it falls under the rubric of "translational research". In these studies, I am interested in understanding the mechanisms of inflammation, airway remodeling, and airway hyper-responsiveness in asthma and chronic obstructive pulmonary disease. These studies are performed in the Airway Clinical Research Center here at UCSF and in the General Clinical Research Unit at the UCSF Parnassus campus where I am an investigator. A major focus of my recent work has been gene expression profiling in tissues obtained at fiberoptic bronchoscopy. Recent applications have included studies of airway smooth muscle structure and phenotype in airway diseases and studies of alveolar macrophage activation in smoking related lung disease. From the purely clinical research perspective, I am a Co-investigator in the NIH/NHLBI COPD Clinical Research Network which is currently designing protocols for multicenter-clinical trials in the therapy of COPD.


Rheumatology

Faculty name: Sharon A. Chung, MD MAS

Contact information: Sharon.chung@ucsf.edu
                                    Office 415-514-1673

Subspecialty/research focus: Translational and genomic studies of vasculitis and systemic lupus erythematosus

Title/description of research projects:

Our goal is to discover genetic, epigenetic, and transcriptional factors that influence autoimmune disease susceptibility and its manifestations. Current projects focused on systemic lupus erythematosus (SLE) include whole genome sequencing and genome-wide association studies, detailed investigations of the major histocompatilibity complex, and DNA methylation studies of specific disease manifestations. My clinical interest is systemic vasculitis, and I direct the UCSF Vasculitis Clinic. Our research activities in vasculitis include exome sequencing, DNA methylation, and RNA-sequencing studies of ANCA-associated vasculitis. The UCSF Vasculitis Clinic is a member of the Vasculitis Clinical Research Consortium (VCRC), and the clinic participates in ongoing VCRC clinical and translational studies.


Faculty name: Jonathan Graf, MD

Contact information: Division of Rheumatology, SFGH
                                    1001 Potrero Avenue, Building 30/Room 3300
                                    San Francisco, CA 94110
                                    Tel: 415-206-8189
                                    Fax: 415-648-8425
                                    jonathan.graf@ucsf.edu
                                    Website: http://rheumatology.ucsf.edu/research/

Subspecialty/research focus: Autoimmune Diseases, Rheumatoid Arthritis, vasculitis, cardiovascular disease risk

Title/description of research projects: The primary focus of our research centers on translational studies related to rheumatoid arthritis, particularly those that take advantage of the UCSF Rheumatoid Arthritis Observational Cohort. Created in 2006, this longitudinal cohort captures real time clinical information from more than 750 patients at each of their clinical encounters across multiple UCSF campuses. The cohort uses a real-time database to record detailed clinical information that is coupled with a biological/serum sample bank linked to each patient. This cohort facilitates clinical and translational studies both within and outside of the UCSF division of rheumatology, including (but not limited to) collaborations that study cardiovascular risk and dyslipidemia, genetics and epigenetics, immunology and osteoclast function, MRI quantification of disease activity, and socio-economic determinants of disparity and depression. We also conduct investigator initiated and industry collaborative early-phase clinical trials of novel therapeutics for rheumatoid arthritis.


Faculty name: Mary C. Nakamura, MD

Contact information: Associate Professor of Medicine in residence
                                   Department of Medicine, Division of Rheumatology
                                   VAMC, Building 2, room 500, 508
                                   Phone: 415-750-2104
                                   Fax: 415-750-6920
                                   mary.nakamura@ucsf.edu

Subspecialty/research focus: Osteoimmunology
                                                  Bone Biology
                                                  Immunology
                                                  Rheumatology

Title/description of research projects:

Our laboratory is interested in the role of innate immune receptors in the regulation of differentiation and function of innate immune cells in normal and pathological states. We have examined innate receptor regulation in natural killer cells for a number of years and recently have focused on the role of innate receptors in the regulation of osteoclasts. These more recent studies focusing on "Immunoreceptor Regulation of Osteoclasts" are now considered part of the evolving field of osteoimmunology, which examines the interactions between the immune system and bone. Osteoclasts are specialized bone resorbing cells that form from myeloid precursor cells, and express a repertoire of innate immune receptors that are critical for osteoclast development and function. Abnormal bone remodeling, secondary to increased osteoclast maturation or activation, contributes to bone destruction in osteoporosis, rheumatoid arthritis and bony metastases. We are currently working to 1) define receptors that mediate activation and inhibition of osteoclast function 2) examine the roles of specific signals in osteoclastogenesis 3) examine the roles of receptors and signals in mouse models of inflammatory bone loss. We are also interested in further defining circulating osteoclast precursors in human disease states and will begin by examining circulating OC precursors in RA patients. The goal of this more translational study will be to specifically address the relationship between circulating osteoclast precursors, disease activity, development of erosions and responses to therapy.


Sports Medicine

Faculty name: Karen B. King, PhD
                         kbking@itsa.ucsf.edu
                         510-231-9448

Subspecialty/research focus: Orthopaedic Mechanobiology

Title of research project: Repetitive loading in degenerative joint disease.

Description of project: Collect and analyze data from an in vivo animal model for repetitive finger joint loading, and prepare & publish manuscript of results and conclusions. Note: Office and laboratory are located in the East Bay at the Richmond Field Station.