Division of Gastroenterology

Training Grant

NIH/NIDDK
GASTROENTEROLOGY TRAINING GRANT
T32 DK007202
07/01/76 - 06/31/12
John M. Carethers, M.D. - Program Director

The Division's NIH Training Grant was initially funded in 1976. The Division has trained several local gastroenterologists in San Diego as well as developed several academicians at University-based medical schools, including some with leadership and administrative positions.

The aim of the three-year research training program is to develop independent investigators who will devote their career to research on fundamental aspects of digestive diseases and train individuals from the adult and pediatric GI programs.

The Training Grant supports, per year

Postdoctoral training involves three years of supervised, self-directed laboratory research aimed at developing the trainee's ability to formulate meaningful scientific questions and hypotheses, design and conduct experiments to test hypothesis, and present results in oral and written form. Laboratory research is performed in the laboratory of a faculty sponsor of the Training Grant and supplemented, as appropriate, by didactic course work.

The predoctoral program for Ph.D. candidates involves research training within the laboratory of a faculty sponsor of the Training Grant under the auspices of the Biomedical Sciences or Molecular Pathology Graduate Programs.

The training faculty includes basic scientists at UCSD and neighboring research institutes where there is close collaboration. The program is designed for graduate students and M.D.s or Ph.D.s who are committed to an academic career in digestive sciences. Special efforts are made to attract minority candidates. At completion, the postdoctoral trainees are competitive for entry level independent funding and predoctoral trainees are highly competitive for outstanding postdoctoral positions.

Research performance sites are located at UCSD, San Diego Veteran Affairs Medical Center (VAMC), La Jolla Institute for Allergy & Immunology (LIAI), Burnham Institute, and The Salk Institute. A list of the Training Grant faculty sponsors is listed below.

 

Training Grant Faculty Sponsors

John M. Carethers. M,D., Program Director - UCSD

Dr. Carethers' laboratory studies the development of colorectal neoplasms. A key area of focus is the clinical consequences of developing tumors with inactivation of the DNA mismatch repair system. The lab has investigated the effect of chemotherapeutic agents on cells with and without an intact mismatch repair system. A second area of focus for the laboratory is the effects of the TGFb superfamily signaling pathways on colorectal cancer. Notably, the lab is investigating activin signaling (biallelically mutated in over 80% of microsatellite unstable colorectal cancers), BMP signaling (mutated in the germline of some juvenile polyposis patients), and TGFb (involved in 75% of colorectal and pancreatic cancers). A final area of focus is on the pathogenesis of hamartomatous polyposis syndromes.

Research training opportunities, in addition to the areas described above, include the study of recognition of altered nucleotides by the DNA mismatch repair system, examining triggers for cell death by the DNA mismatch repair system, studying the interplay of TGFb signaling with other mitogenic pathways for colon cancer, and 3-dimensional modeling of hamartomatous polyps. All of these projects are excellent for teaching future trainees in research in gastroenterology. Trainees will develop expertise in molecular biology that deals with genetic and epigenetic events, in vitro and in vivo techniques of gene manipulation, microsatellite analysis, analysis and correlation with human disease epidemiology, as well as understanding the broad basis of colon cancer biology. Trainees participate in weekly lab meetings and journal clubs.

Kim E. Barrett, Ph.D. - UCSD

Dr. Barrett's interests involve epithelial transport and barrier function in human health and disease and its inter- and intracellular regulation. The laboratory has a primary focus on chloride secretory mechanisms in the gastrointestinal tract. Ongoing studies are characterizing intracellular signaling events intrinsic to the epithelium that limit calcium-dependent chloride secretion. Dr. Barrett's work uses a broad range of techniques from molecular approaches and studies in cell lines to work using animal subjects or human tissue specimens. All projects in the laboratory are available for trainee participation. Trainees are assigned an independent area, in consultation with Dr. Barrett, and then play an integral role in matters of experimental design, conduct of the research program, and preparation of findings for presentation in both written and oral formats. Dr. Barrett has considerable experience in hosting trainees at all levels and has an active program of lab meetings and informal journal clubs that facilitate communication among lab members and develop presentation skills.

David Broide, M.D.

Dr. Broide's laboratory studies the role of eosinophils in diseases such as asthma and eosinophilic esophagitis. Studies of eosinophilic esophagus are performed in a mouse model of egg-induced eosinophilic esophagitis which is associated with eosinophilic inflammation of the esophagus and remodeling of the esophagus. The use of mutant mice lacking signle genes or neutralizing Abs, allows dissection of the role particular genes or gene products play in the pathogenesis of eosinophilic esophagitis.

Hilde Cheroutre, Ph.D. - LIAI

Dr. Cheroutre's research focuses predominantly on the biology of intra-epithelial lymphocytes (IEL), their development and function and in understanding regulatory mechanisms involved in controlling differentiation and regulation of T cells migrating and residing in the intestinal mucosa. The ultimate goal of her research is to understand the biology of mucosal TCRab T cells that provide controlled protection without self-destruction. Trainees have the opportunity to design and execute experiments in vitro and in vivo that understand the function of the IELs.

Mario Chojkier, M.D. - UCSD/VAMC

Dr. Chojkier studies the response to liver injury, hepatic stellate cell activation causes excessive liver fibrosis resulting in cirrhosis. His laboratory has been investigating whether RSK-inhibitory peptides would block stellate cell activation and liver fibrosis. Trainees would further investigate the molecular pathways responsible for the activation of caspase 8 by C/EBPb-Ala217 as well as the optimal peptido-mimetic compounds for inhibition of stellate cell activation in liver fibrosis.

Edward Dennis, M.D. - UCSD

Dr. Dennis' laboratory is focused on understanding the regulation of lipid second messengers and signal transduction processes and especially the role of various phospholipases in their generation. Dr. Dennis' laboratory also designs and synthesizes chemical inhibitors of phospholipase A2. In summary, this laboratory utilizes organic synthetic approaches, enzyme kinetics, molecular biology, site-specific mutagenesis, cell and tissue culture, and high-resolution NMR techniques, as well as, traditional biochemical approaches in attacking phospholipase and membrane problems. Trainees will be involved in one or more of these projects, will be closely mentored, and well learn organic synthetic approaches, enzyme kinetics, molecular biology aimed at site-specific mutagenesis, tissue culture, and high-resolution NMR techniques as well as traditional biochemical approaches in attacking phospholipase and membrane problems.

Hui Dong, M.D. - UCSD

Dr. Dong works in the area of intestinal epithelial physiology, especially the novel roles of membrane receptors and ion channels in the regulation of duodenal epithelial ion transport. Research conducted in this lab includes: (1) expression and function of estrogen receptors and 5-HT receptors in duodenal epithelium, (2) cellular and molecular mechanisms of Ca2+-mediated duodenal CI- and HCO3- secretion, and (3) novel roles of K+ channels and CIC-2 channels in the regulation of duodenal HCO3- secretion. Trainees will learn all aspects of this physiological and molecular biology research.

Lars Eckmann, M.D. - UCSD

Dr. Eckmann's overall research interests are in the cellular and molecular pathogenesis of infections with enteric pathogens and the mechanisms underlying the regulation of intestinal inflammation. Studies focus on the use of animal models of intestinal infection and inflammation, and employ molecular, microbiological, histological approaches to elucidate the key genes and cellular and molecular mechanisms that govern intestinal host defenses against enteric pathogens and regulate inflammatory responses in the gastrointestinal tract. Current studies define host defense mechanisms against the protozoan pathogen Giardia and the bacterial pathogens Escherichia coli and Salmonella. Trainees will have an opportunity to learn in vivo approaches for studying host interactions with microbial pathogens.

Marilyn Farquhar, Ph.D. - UCSD

Dr. Farquhar's research is focused on identification of components of G-protein mediated signaling pathways controlling membrane trafficking along the exocytic and endocytic pathways. Dr. Farquhar's laboratory has recently identified several new proteins that are components of novel G protein-mediated signaling pathways. Dr. Farquhar's laboratory is using the two-hybrid system and affinity chromatography to identify and characterize novel proteins that interact with GTP-binding proteins and specific regions of resident Golgi proteins. Students in Dr. Farquhar's laboratory select and plan their project in an area of active ongoing laboratory investigation. Graduate students and postdoctoral fellows have the opportunity to learn and develop their expertise in cell biology in a superb teaching environment.

Theodore Freidmann, M.D. - UCSD

The Friedmann laboratory continues its studies of the neuro-developmental disease Lesch Nyhan Disease. They are concentrating on microarray and proteomic characterization of human fibroblasts derived from LND patients and of affected brain regions of the HPRT gene knockout mouse model of the disorder. The Friedmann laboratory is also continuing its major study of the molecular mechanisms of growth enhancement by the growth factor IGF-1 in cultured cells and in mice in vivo. Training opportunities for pre- and post-doctoral trainees are in the area of gene therapy working with Dr. Friedmann directly or in collaboration with other training faculty.

Richard L. Gallo, M.D., Ph.D. - UCSD

Dr. Gallo's laboratory is interested in understanding the basic mechanisms of epithelial defense and repair. Currently, the major focus is in investigating the function and regulation of antimicrobial peptides. Through the use of a variety of biochemical and molecular techniques they have found that the skin produces cationic peptides during the early response to injury. Another interest of the group is the function of tissue glycosaminoglycans as immune signaling molecules and co-factors to aid in wound repair. Dr. Gallo's group has an active journal club and seminar series as part of its educational program. Trainees will have the opportunity to work on projects involving innate defense molecules relevant to epithelial cell defense using in vitro and in vivo systems.

Pradipta Ghosh, M.D. - UCSD

Dr. Ghosh's laboratory studies focus on cell biology of signal transduction with a special emphasis on identification and characterization of signal amplification switches that drive key cellular processes such as migration, proliferation, survival, apoptosis, secretion, etc. In most cases, while timely and restricted amplification of signals is essential to tide over stress or injury in physiologic conditions (such as promote healing in any epithelial wounds/ulcers), sustained enhancement/amplification of signals (in response to growth factors/agonists) heralds oncogenesis and cancer metastasis. Similarly, abnormal signal amplification is a key feature during an over zealous inflammatory response during wound healing and can be associated with yet another undesired outcome, i.e., fibrogenesis (cardiac fibrosis after myocardial infarction, all causes of liver cirrhosis, pulmonary and renal fibrosis); thereby distorting normal anatomy and impairing normal functions. Dr. Ghosh's laboratory seeks to gain insights into how incoming signals are amplified in an unrestricted fashion to drive the key cellular processes (secretion, autophagy, growth, proliferation, migration) in health and disease, and identify novel signal-amplification switches/interfaces within key signaling pathways which can also serve as therapeutic targets. Students, technicians, and postdoctoral fellows in Dr. Ghosh's laboratory receive close training and guidance in any area of active ongoing laboratory investigation they wish to follow. The opportunities to gain expertise, learn, discover, and have fun in the process are limitless. The laboratory's location (George Palad Laboratories for Cellular and Molecular Medicine) adds to this enriched research environment.

 

Frances Gillin, Ph.D. - UCSD

Dr. Gillin's research is focused on Giardiasis which remains a major global cause of waterborne diarrheal disease contributing greatly to the burden of malnutrition and malabsorption leading to childhood mortality. Worldwide, diarrheal diseases are second only to HIV as a cause of death from infections. Graduate students and postdoctoral fellows will select their project in the area of Giardia biology and Giardia-host interaction with Dr. Gillin and actively take part in the laboratory's training and educational activities.

Christopher K. Glass, M.D., Ph.D. - UCSD

Dr. Glass' laboratory investigates the mechanisms by which sequence-specific transcription factors regulate the development and function of macrophages. A major focus is on members of the nuclear receptor, AP-1 and Ets families of transcription factors. The laboratory uses a combination of biochemical, cellular, and in vivo model systems and incorporating macrophage-specific knockouts, microarray technologies and bioinformatic approaches to unravel the contributions of specific factors to the development of specialized macrophage functions and the pathogenesis of inflammatory diseases.

Donald Guiney, M.D. - UCSD

Dr. Guiney's laboratory studies the pathogenesis of infection by two gastrointestinal pathogens: Salmonella strains and Helicobactor pylori. Both projects emphasize the interactions of bacterial virulence factors with critical host cells involved in the disease process and the immune response. The Salmonella project focuses on the effects of bacterial virulence proteins transported into infected host cells. Work on H. pylori concentrates on the ability of the organism to activate the innate immune response in epithelial cells as well as macrophages and dendritic cells. Trainees will learn in vivo and in vitro techniques to study interactions between host and bacteria.

Samuel Ho, M.D. - VAMC

Dr. Ho's research programs include both clinical and basic science investigations. Clinical programs include investigations in the treatment and management of chronic hepatitis C and chronic inflammatory conditions of the stomach and intestines. Dr. Ho is the Director of the Minneapolis/San Diego Hepatitis C Resource Center (HCRC). This is one of four such centers in the VA system dedicated to developing best practices for patients with hepatitis C and to providing training and education for clinicians working with hepatitis C patients. Dr. Ho continues as Director of the Minneapolis Hepatitis C Resource Center and expanded the program to include San Diego. For future trainees, both the laboratory and clinical hepatitis C center are ideal environments to nurture GI trainees for a future academic career in gastroenterology. In the laboratory, they will learn general molecular biology techniques, cell culture, cell cloning, and transfection, gene sequencing, flow cytometry, animal models as well as learning about basic gastrointestinal epithelial biology and the effects of acute and chronic inflammation. The clinical hepatitis C center will be staffed by a number of outcome research personnel and there are numerous clinical projects to become involved with.

Hal M. Hoffman, M.D. - UCSD

A main focus of Dr. Hoffman's laboratory is the identification of genes for rare inherited disorders. In 2001, the laboratory identified CIAS1, a gene that is responsible for three autosomal dominant inflammatory disorders. The discovery led to a novel effective treatment for these patients. Currently, the laboratory is investigating the normal function of this gene in human monocytes and genetically modified mice. Also, studies on identification of the gene for a rare autosomal recessive diarrheal disease, congenital tufting enteropathy. Trainees will learn a multitude of genetic techniques, as well as determine functional aspects of found genes.

Paul Insel, M.D. - UCSD

Dr. Insel's laboratory is involved in studies of signal transduction in epithelial cell systems, in particular, by G protein-coupled receptors (e.g., P2Y and prostanoid receptors). Current work in the laboratory emphasizes MDCK cells, which possess both P2Y and prostanoid receptors as do billiary duct epithelial cells and various other gastrointestinal tract epithelial cells. Other work in the laboratory focuses on the ability of P2Y and adenosine receptors to regulate leukocyte function, especially as related to inflammatory stimuli. Trainees who work in the Insel laboratory will investigate cellular and biochemical mechanisms involved in the regulation and activation of GTP binding proteins, adenylyl cyclase, phosphodiesterases, protein kinases, including stoichiometry of expression of components in signaling microdomains. Other work involves regulation of adenylyl cyclase isoforms, studies of mechanisms involved in "cross talk" for signal transduction systems (e.g., adenylyl cyclase via Ca2+, nitric oxide, and protein kinase C) and by different classes of G protein-coupled receptors. The laboratory uses molecular biological, cell biological, and biochemical techniques for its studies. Trainees will select a project that will entail exposure to multiple experimental approaches and methods. Trainees participate in all educational and intellectual activities of the laboratory, including weekly research conferences and a Signal Transduction Journal club.

Barbara Jung, M.D. - UCSD

Dr. Jung investigates the role of activin signaling in colon cancer. Both patient-based and mechanistic studies are being utilized. Trainees have the opportunity to be true translationists, combining classic genetic and biochemical approaches in studying colorectal cancer and linking the findings with real patient epidemiological data to determine the biological consequences as well as potential therapeutic approaches to improve the disease.

Martin F. Kagnoff, M.D. - UCSD

Dr. Kagnoff's laboratory focuses on mechanisms by which epithelial cells act as an integral component of the mucosal immune system and mechanisms important in the pathogenesis of intestinal mucosal inflammation. He has made a number of important discoveries showing how the epithelium can function in the cross talk between host innate and acquired immune responses. His laboratory uses molecular and cellular techniques and a range of in vitro model systems to address these issues. Dr. Kagnoff's laboratory uses microbial pathogens to probe and explore the range of epithelial cell responses to different types of microbial pathogens, how those responses are signaled and regulated, and their influence on mucosal immune and inflammatory processes. Model systems include the use of relevant non-invasive and epithelial cell invasive enteric pathogens. His laboratory is an expert in the use of state-of-the-art gene discovery based tools and transgenic and conditional gene knockout approaches to study epithelial signaling mechanisms and the influence of those mechanisms on mucosal inflammation and wound healing. Trainees have an opportunity to work in both in vitro and in vivo systems using these state-of-the-art approaches to answer important questions relating to mucosal immunity and its role in intestinal inflammatory diseases. The laboratory maintains an active seminar and journal club program and collaborates closely with other laboratories interested in host-microbial interactions and mucosal inflammation, which provides a valuable experience for trainees.

Michael Karin, Ph.D. - UCSD

The Karin Laboratory studies potentially pharmacologically-regulated signaling pathways. He has several generated mouse models, both general and tissue-specific, for which to characterize the importance of the inflammatory cascade. Dr. Karin has also produced transgenic mice that express a degradation resistant mutant of NF-kB in various cell types. Dr. Karin also studies the signaling pathways leading from the TNF and IL-1 receptors to activation of various MAP kinases, including JNKs and p38. Trainees are able to participate in studies on the function of these kinases in various inflammatory and immune responses, as well as, in the development of intestinal inflammation. Dr. Karin's studies are ideal for fellows in the gastroenterology training program interested in mucosal inflammation and epithelial cell and lamina propria immunocyte biology. Trainees will be able to participate in Dr. Karin's studies of the IkB kinase(s)and their role in inflammatory and autoimmune diseases and cancer.

Richard Kolodner, Ph.D. - UCSD

Dr. Kolodner's laboratory is interested in the genes and proteins that function in genetic recombination, DNA repair events that act in genetic recombination and in overall maintenance of genome stability. Their ongoing projects include the use of the yeast, Saccharomyces cerevisiae, to study the genes and proteins that function in recombination and repair, the establishment of mutant mice that are defective for DNA repair, the study of the genetics of Hereditary Nonpolyposis Colon Cancer (HNPCC), and other cancer susceptibility syndromes that result from DNA repair defects. Trainees have been major participants for many of these projects and are involved in all aspects of the research.

Mitchell Kronenberg, Ph.D. - LIAI

Dr. Kronenberg has studied the TCR diversity of the donor derived T cells in the intestine of the diseased SCID recipients by immunoscope (CDR3 length) analysis and sequencing of TCR beta chains. Current experiments explore the roles of Ig family and TNF family costimulatory molecules. Students have the opportunity to work closely with Dr. Kronenberg in selecting and designing their project and an opportunity to learn state-of-the-art molecular and in vivo animal model approaches to study important questions relevant to mucosal inflammation. LIAI maintains an excellent seminar and journal club program that emphasizes graduate student and postdoctoral training and has now moved onto the UCSD campus.

Joel Lavine, M.D. - UCSD

Dr. Lavine's primary clinical research interest involves non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) in children and adults. Dr. Lavine's group has demonstrated that NASH is the most relevant liver disease in children, that pediatric NASH histopathology differs from adult NASH, and that NASH prevalence and features segregate by gender and ethnicity. Further, his group has recognized key clinicopathological correlates and piloted the initial clinical treatment trials which serve as the treatment arms for the NIDDK-sponsored multi-center trial underway as part of the NASH Clinical Research Network. Future trainees on the training grant submitted here may be interested in some novel projects being performed in collaboration with Dr. Ron Evans from The Salk Institute. Drs. Evans and Lavine are investigating the role of nuclear hormone receptor superfamilies in NASH and how potential polymorphisms in transcriptional factors may influence the development, progression, and response to treatment in NASH. Other trainees may be interested in collaborations studying free fatty acid metabolomics and the role of sundry unbound FFAs in pathogenesis or the role of oxidative stress as a result of co-morbid obstructive sleep apnea.

Rohit Loomba, M.D.

 

 

Ravinder Mittal, M.D. - UCSD/VAMC

The research performed in Dr. Mittal's laboratory focuses on two areas: (1) esophagus and (2) pelvic floor. With regards to the esophagus, physiology, and pathophysiology of esophageal motor disorders and visceral sensation is being evaluated using novel methodologies. Physiologic, pharmacological, and clinical studies are being conducted to answer the questions related to pathophysiology of esophageal motor disorder and esophageal sensation. The techniques being utilized to answer these questions are pressure recordings, electrical signal recordings, ultrasound imaging, isolated muscle strip preparation and immunohistochemistry studies of the neurotransmitters of the GI tract. Some of these studies are being conducted in humans and other studies in animals. Dr. Mittal is currently exploring new methods of studying esophageal motility that utilizes high frequency ultrasound probes. Dr. Mittal's laboratory is also exploring the physiology and pathophysiology of pelvic floor function. For these studies, physiologic monitoring and various types of imaging is being done in human and animal models to understand the physiologic and pathophysiologic role of puborectalis muscle in fecal and urinary continence. Trainees will have the opportunity to develop a project within these areas of study and will actively participate in all the educational aspects of this laboratory.

Eyal Raz, M.D. - UCSD

Dr. Raz's laboratory analyzes the interaction of innate immunity with microbial agents. In particular, he studies the role of microbial products in the activation and inhibition of mucosal inflammation. Recently, they have characterized the immune profile induced by TLR ligands, such as LPS, lipopeptides or bacterial DNA at mucosal sites, and analyzed the impact of these ligands on experimental colitis (e.g., DSS-, TNBS-, and oxasolone-induced colitis). Future projects will identify the mechanisms behind these diverse effects and its relationship to health and disease states. His laboratory offers excellent projects and an exciting environment for postdoctoral trainees with an interest in learning and applying state-of-the-art approaches to translation al science.

Silvia Resta, M.D., Ph.D. - UCSD

Dr. Resta-Lenert's long-term research objective is to provide better understanding of the interactions of the intestinal mucosal with the commensal microbiota and enhance the scientific basis for the use of alternative medicine treatments in chronic inflammatory diseases involving the gastrointestinal tract. The research of her group focuses on: (1) the role of commensal organisms in modulating growth and differentiation of the gut epithelium; (2) understanding the mechanisms underlying modulation of epithelial transport, absorption, and barrier function by commensal and probiotic bacteria; (3) the role of commensals in the development of innate immunity and allergy, (4) the role of probiotics and prebiotics in promoting a restorative milieu in gastrointestinal disease and colon cancer prevention, and (5) role of commensal bacteria on the aging processes. Trainees will learn in vitro and in vivo techniques and apply them to the understanding of commensal bacteria in regulating inflammation.

Robert C. Rickert, Ph.D. - Burnham Institute

Dr. Rickert's research focuses on normal and aberrant B lymphocyte function. A major effort in the lab is to utilize conditional gene targeting in mice as well as signal transduction and cell culture approaches to characterize the key intracellular signalling pathways (e.g. PI3-kinase and NF-kB) that direct B cell differentiation. From these efforts, we have gained insights into the molecular underpinnings of selected B cell malignancies and autoimmune conditions. Of particular interest is understanding the cellular and molecular events that govern the germinal center response, resulting in the generation of high-affinity memory B cells or antibody-producing cells. Studies in this area address IgM versus IgG signaling, coreceptor (CD19, CD21, FcgRIIB) function and cytokine receptor signaling. Since B cells are generally non-adherent cells, we are also interested in understanding the molecular basis of B cell homing to particuluar in vivo niches. There are training opportunities available in all of the outlined areas. Trainees will acquire technical expertise in molecular and cellular immunology, signal transduction and working with mouse models of huma diseas as they relate to understanding autoimmunity and lymphomagenesis. Trainees participate in weekly lab meetings and journal clubs, as well as local and national meetings.

Jeffrey Schwimmer, M.D. - UCSD

Dr. Schwimmer focuses on the field of pediatric obesity. Dr. Schwimmer's research addresses why do obese children differ so greatly in the number, type, and severity of co-morbid conditions? Obesity is a major risk factor for nonalcoholic fatty liver disease (NAFLD) in children and because of the high prevalence of childhood obesity it has become the most common cause of chronic liver disease in children. Students and trainees working in the Schwimmer laboratory are able to participate in local and national studies. Current trainee projects include studies of: (1) quality of life in NAFLD, (2) the association of NAFLD and cardiovascular events, (3) dietary risk factors for NAFLD, and (4) adipocytokines in obesity and fatty liver.

Susan S. Taylor, Ph.D. - UCSD

Dr. Taylor uses a multi-disciplinary approach to probe the structure and function of one of the simplest members of the protein kinase family, cAMP-dependent protein kinase (cAPK). Dr. Taylor is studying the dynamic properties of PKA in the cell using recombinant and fluorescence methods. Trainees will learn state-of-the-art molecular biology to understand the structure and function of protein kinases.

Ajit Varki, M.D. - UCSD

Dr. Varki's research interests are focused on a family of sugars called the Sialic acids, and their roles in biology, evolution, and disease. Sialic acids are found at the outermost position on the glycan chains of all vertebrate cell surfaces and glycoproteins, and the highest levels are found in the nervous system. Currently, active projects are relevant to the roles of Sialic acids in microbial infection; the regulation of the immune response; the progression of cancer, and unique aspects of human evolution. Trainees have the opportunity to work with in vitro and in vivo models to understand the function of Sialic acids.

Geoffrey Wahl, Ph.D. - The Salk Institute

Dr. Wahl's studies center around the mechanisms that insure faithful reproduction and segregation of DNA and how such safeguards are abrogated during cancer progression. A major focus concerns the mechanisms by which the p53 tumor suppressor insures the integrity of the genome. Over the past several years, Dr. Wahl has devised strategies to investigate how these extrachromosmal molecules are transmitted to daughter cells at mitosis. Dr. Wahl's laboratory at The Salk Institute offers a number of areas for projects by trainees that will provide excellent training in basic mechanisms of cell growth regulation directly relevant to gastrointestinal neoplasia.

Jason X-J Yuan, M.D., Ph.D. - UCSD

The overall interest of Dr. Yuan's laboratory is cell physiology and pathophysiology, with particular emphasis on the regulation of excitation-contraction coupling in vascular smooth muscle and the cellular and molecular mechanisms of hypoxic pulmonary vasoconstriction and idiopathic and thromboembolic pulmonary hypertension. By using the combined techniques of patch clamp, digital imaging fluorescence microscopy and molecular biology, members are currently studying the roles of ion channels and intracellular Ca2+ in regulating vasomotor tone, and vascular smooth muscle proliferation and apoptosis. Furthermore, whether the endothelium-derived relaxing factors results in vasodilation and apoptosis by regulating function and expression of ion channels is also being investigated.

Research training opportunities, in addition to the areas described above, include the profiling of ion channels in stem cells and the regulation of intracellular Ca2+ by vasoactive and mitogenic agonists. These projects are excellent for teaching future trainees in research in vascular physiology. Trainees develop expertise in physiology and cellular and molecular biology as it relates to smooth muscle electrophysiology, as well as gain a broad understanding of the mechanisms regulating pulmonary vascular smooth muscle contraction and proliferation in various forms of pulmonary hypertension. Trainees work under the supervision of scientists within the lab, and are expected to participate inweekly lab meetings.