Training Grant Faculty Research Interests

Bunnett, Nigel

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Research Interests

My laboratory studies the mechanisms that switch-on and switch-off inflammation and pain. Inflammation protects against infection, and the sensation of pain allows organisms to avoid stimuli that would otherwise cause injury. However, inflammation must be tightly controlled since dysregulated, exaggerated inflammation causes disease and pain. The mechanisms that initiate and terminate inflammation and pain are poorly understood, and consequently the therapies are inadequate and often associated with detrimental side effects. Our work focuses on the role of proteolytic enzymes as “molecular switches” that initiate and terminate signaling by mediators of inflammation and pain. Proteases that act at the cell-surface and in endosomes, lysosomes and proteasomes cleave neuropeptides, G-protein coupled receptors and ion channels and thereby control signaling by major mediators of inflammation and pain transmission.

Selected Publications

• Amadesi S, Nie J, Vergnolle N, Cottrell GS, Grady EF, Trevisani M, Manni C, Geppetti P, McRoberts JA, Ennes H, Davis JB, Mayer EA & Bunnett NW. (2004). Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia. J Neurosci 24, 4300-4312.
• Grant AD, Cottrell GS, Amadesi S, Trevisani M, Nicoletti P, Materazzi S, Altier C, Cenac N, Zamponi GW, Bautista-Cruz F, Barajjas Lopez C, Joseph E, Levine JD, Liedtke W, Vanner S, Vergnolle N, Geppetti P & Bunnett NW. (2006). Protease-Activated Receptor 2 Sensitizes the Transient Receptor Potential Vanilloid 4 Ion Channel to Cause Mechanical Hyperalgesia. J Physiol.
• Jacob C, Cottrell GS, Gehringer D, Schmidlin F, Grady EF & Bunnett NW. (2005). c-Cbl mediates ubiquitination, degradation, and down-regulation of human protease-activated receptor 2. J Biol Chem 280, 16076-16087.
• Steinhoff M, Vergnolle N, Young SH, Tognetto M, Amadesi S, Ennes HS, Trevisani M, Hollenberg MD, Wallace JL, Caughey GH, Mitchell SE, Williams LM, Geppetti P, Mayer EA & Bunnett NW. (2000). Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med 6, 151-158.
• Vergnolle N, Bunnett NW, Sharkey KA, Brussee V, Compton SJ, Grady EF, Cirino G, Gerard N, Basbaum AI, Andrade-Gordon P, Hollenberg MD & Wallace JL. (2001). Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway. Nat Med 7, 821-826.

Bull, Laura

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Research Interests

The main focus of my laboratory is on increasing our understanding of the biology of the liver and enterohepatic circulation in health and disease, through the application of genetic approaches. Studies of several liver diseases are ongoing in my laboratory, and each at a different stage. These projects include:

1. Genetic studies of Familial hypercholanemia (FHCA).
2. Study of disease caused by mutation in FIC1(ATP8B1), and characterization of mouse models of ATP8B1 disease.
3. Genetic studies of lymphedema-cholestasis syndrome (LCS, Aagenaes syndrome).
4. Evaluation of genetic factors influencing susceptibility to 'secondary' liver diseases, including drug-induced cholestasis.

Selected Publications

• Carlton VE, Harris BZ, Puffenberger EG, Batta AK, Knisely AS, Robinson DL, Strauss KA, Shneider BL, Lim WA, Salen G, Morton DH, Bull LN. (2003) Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT. Nature Genetics, vol 34, pp. 91-96.
• Bull, L.N., Roche, E., Song, E.J., Pedersen, J., Knisely, A.S., van der Hagen, C.B., Eiklid, K., Aagenaes, O., Freimer, N.B. (2000) Mapping of the locus for Cholestasis-Lymphedema Syndrome (Aagenaes Syndrome) to a 6.6.cM interval on chromosome 15q. American Journal of Human Genetics, vol 67, pp. 994-999.
• Bull, L.N., Juijn, J.A., Liao, M., van Eijk, M.J.T., Sinke, R.J., Stricker, N.L., DeYoung, J.A., Carlton, V.E.H., Baharloo, S., Klomp, L.W.J., Abukawa, D., Barton, D.E., Bass, N.M., Bourke, B., Drumm, B., Jankowska, I., Lovisetto, P., McQuaid, S., Pawlowska, J., Tazawa, Y., Villa, E., Tygstrup, N., Berger, R., Knisely, A.S., Houwen, R.H.J., Freimer, N.B. (1999) Fine-resolution mapping by haplotype evaluation: the examples of PFIC1 and BRIC. Human Genetics, vol 104, #3, pp 241-248.
• Strautnieks, S.S., Bull, L.N., Knisely, A.S., Kocoshis, S.A., Dahl, N., Arnell, H., Sokal, E., Dahan, K., Childs, S., Ling, V., Tanner, M.S., Kagalwalla, A.F., Németh, A., Pawlowska, J., Baker, A., Mieli-Vergani, G., Freimer, N.B., Gardiner, R.M., Thompson, R.J. (1998). A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nature Genetics, vol. 20, #3, pp.233-238.
• Bull, L.N., van Eijk, M.J.T., Pawlikowska, L., DeYoung, J.A., Juijn, J.A., Liao, M., Klomp, L.W.J., Lomri, N., Berger, R., Scharschmidt, B.F., Knisely, A.K., Houwen, R.H.J., Freimer, N.B. (1998). A gene encoding a P-type ATPase is mutated in two forms of hereditary cholestasis. Nature Genetics, vol. 18, #3, pp. 219-224.

Corley, Douglas

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Research Interests

Gastrointestinal cancers, drug safety, and reflux disease.

Selected Publications

• Corley DA. Chemoprevention in Barrett's Esophagus: Are we There yet, Are we There yet...? Clin Gastroenterol Hepatol. 2009 Sep 16.
• He T, Corley DA, Lu M, Di Spigna NH, He J, Nackashi DP, Franzon PD, Tour JM. Controllable molecular modulation of conductivity in silicon-based devices. J Am Chem Soc. 2009 Jul 29;131(29):10023-30.
• Corley DA, Kubo A, DeBoer J, Rumore GJ. Diagnosing Barrett's esophagus: reliability of clinical and pathologic diagnoses. Gastrointest Endosc. 2009 May;69(6):1004-10.
• Wong RJ, Corley DA. Survival differences by race/ethnicity and treatment for localized hepatocellular carcinoma within the United States. Dig Dis Sci. 2009 Sep;54(9):2031-9.
• Kubo A, Levin TR, Block G, Rumore GJ, Quesenberry CP Jr, Buffler P, Corley DA. Alcohol types and sociodemographic characteristics
• as risk factors for Barrett's esophagus. Gastroenterology. 2009 Mar;136(3):806-15. Kubo A, Levin TR, Block G, Rumore GJ, Quesenberry CP Jr, Buffler P, Corley DA. Dietary antioxidants, fruits, and vegetables and the risk of Barrett's esophagus. Am J Gastroenterol. 2008 Jul;103(7):1614-23.
• Mahadevan U, Sandborn WJ, Li DK, Hakimian S, Kane S, Corley DA. Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California. Gastroenterology. 2007 Oct;133(4):1106-12.

Cyster, Jason

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Research Interests

The rapid induction of protective antibodies is critical for host defense against pathogens. Reciprocally, unwanted antibody responses against self-components (antigens) are a cause of autoimmune disease. To mount antibody responses, antigen-specific B and T cells that may be as rare as 1 in 100,000 cells must first encounter the antigen and then interact with each other. These encounters occur within peripheral lymphoid organs - lymph nodes, spleen, and mucosal lymphoid tissues - but the mechanisms that control lymphoid cell migration and that promote interactions between rare antigen-specific cells are far from understood. Major goals: (i) define the molecular cues that guide B and T cell migration and interactions in lymphoid organs during the immune response; (ii) characterize selection events required for induction of high affinity antibody responses; (iii) determine how autoreactive B cells are regulated.

Selected Publications

• Allen CDC, Okada T, Tang HL, Cyster JG. Imaging of Germinal Center Selection Eventds During Affinity Maturation. Science 2007;315, 528-31.
• Lesley R, Kelly LM, Xu Y, Cyster JG. Naïve CD4 T cells constitutively express CD40L and augment autoreactive B cell survival. Proc Natl Acad Sci 2006;103, 10717-22.
• Schwab S, Pereira JP, Matloubian M, Xu Y, Huang Y, Cyster JG. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 2005;309, 1735-1739.
• Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, Allende ML, Proia RL, Cyster JG. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 2004;427, 355-360

Holly, Elizabeth

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Research Interests

For 20 years, she has studied the epidemiology of cancer. Dr. Holly is PI of large NCI grants to study the Molecular Epidemiology of non-Hodgkin Lymphoma and the Molecular Epidemiology of Pancreatic Cancer, and the PI of other NCI grants. She is an author of more than 170 scientific reports and a co-author of the text, Designing Clinical Research, now in its second edition. Principal research interests include the epidemiology of: non-Hodgkin lymphoma, pancreatic cancer, anal cancer precursor lesions/HPV, melanoma, and of childhood brain tumors.

Selected Publications

• Tranah GJ, Bracci PM, Holly EA. Domestic and farm-animal exposures and risk of non-Hodgkin's lymphoma in a population-based study in the San Francisco Bay Area. Cancer Epidemiol Biomarkers Prev. 2008 Sep;17(9):2382-7.
• Duell EJ, Bracci PM, Moore JH, Burk RD, Kelsey KT, Holly EA. Detecting pathway-based gene-gene and gene-environment interactions in pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2008 Jun;17(6):1470-9.
• Lee JS, Bracci PM, Holly EA. Non-Hodgkin lymphoma in women: reproductive factors and exogenous hormone use. Am J Epidemiol. 2008 Aug 1;168(3):278-88. Epub 2008 Jun 10.

Korn, W. Michael

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Research Interests

Major aim of our work is the rational design of targeted combination therapies for GI cancer. The projects exploring the systems biology of cancer and have a strongly translational angle. We utilize cutting edge technologies and collaborate with leading scientists to design novel cancer therapies based on an in-depth understanding of cancer signal transduction networks. There are currently two main research tracks:

• Analysis and prediction of pathway responses to targeted inhibition of the EGF- receptor pathway in esophageal and breast cancer. Computer models of signaling networks are being developed and the anti-tumor efficacy of inhibition of critical molecules within these networks is being explored.
• Regulation and function of the human coxsackie-adenovirus receptor CAR. We discovered novel mechanisms of regulation of CAR, which is mission- critical for the success of adenovirus-based cancer treatments. We are investigating the possibility of pharmacological receptor restoration on cancer cells in order to increase the therapeutic efficacy of these viral agents.

Selected Publications

• Korn WM, Macal M, Christian C, Ding R-X, Rauen KA, Warren RS, Ferrell L., Expression of the Coxsackievirus and Adenovirus Receptor in gastrointestinal tumors correlates with tumor differentiation. Cancer Gene Therapy, 2006; 13:792-7
• Lacher M, Anders M, Oft M, Balmain A, Korn WM, TGF? receptor inhibition enhances adenoviral infectivity of carcinoma cells via up-regulation of CAR consequent to mesenchymal-epithelial-transition. Cancer Research, Cancer Res. 2006;66:1648-57.
• Au T, Thorne S, Korn WM, Sze D, Kirn D, Reid TR. Minimal hepatic toxicity pf ONYX-015: spatial restriction of CAR receptor in normal liver. Cancer Gene Therapy, 2007;14:139-150.

Lanier, Lewis

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Research Interests

Liver-related work in the Lanier lab focuses on the activating NKG2D-DAP10 receptor and its ligands. Previously, our group has shown that NKG2D ligands are constitutively expressed in the liver, and expression is increased during chemically- or virally-induced hepatitis. Studies are underway to explore whether NKG2D activation of NK cells or T cells contributes to the pathogenesis of viral hepatitis. This is being accomplished by experiments involving antibody blockade of NKG2D and by use of DAP10-deficient and DAP12-deficient mice. In addition, we are collaborating with Dr. Averil Ma to examine the effects of IL-15 on NKG2D expression and signaling in T cells.

Selected Publications

• Vilarinho S, K Ogasawara, S Nishimura, LL Lanier, JL Baron. Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to hepatitis B virus. Proc Natl Acad Sci USA, 2007;104:18187-18192.
• Lanier LL. Evolutionary struggles between NK cells and viruses. Nat Rev Immunol 2008;8:259-268.
• Rosen DB, W Cao, DT Avery, SG Tangye, Y-J Liu, JP Houchins, LL Lanier. Expression and function of LLT1, a ligand of human NKR-P1A, on activated B cells and dendritic cells. J Immunol 2008;180:6508-6517.
• Sun, J.C. and L.L. Lanier. 2008. Tolerance of NK cells encountering their viral ligand during development. J. Exp. Med. 205:1819-1828.
• Sun, J.C. and L.L. Lanier. 2008. Cutting Edge: Viral infection breaks NK cell tolerance to "Missing Self". J. Immunol. 181:7453-7457.
• Orr, M.T., J.C. Sun, D.G.T Hesslein, H. Arase, J.H. Phillips, T. Takai, and L.L. Lanier. 2009. Ly49H signaling through both DAP10 and DAP12 is required for optimal NK cell responses to mouse cytomegalovirus infection. J. Exp. Med. 206:807-817.
• Sun, J.C., J.N. Beilke, and L.L. Lanier. 2009. Adaptive immune features of Natural Killer cells. Nature 457:557-561.

Locksley, Richard

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Research Interests

The immune system is a complex organization of many cell types whose activities are orchestrated through controlled expression and secretion of cytokines and other mediators. We have produced cytokine reporter mice that allow the visualization of immune system function during a variety of infectious and inflammatory diseases. Our primary interests involve efforts to understand allergic and anti-helminth immunity, which constitute major public health issues in both developed and developing countries. The major goals of the laboratory involve identification of molecular processes that drive eosinophil and basophil responses in tissues; that activate macrophages to the ‘alternatively activated’ state associated with allergic inflammation; that promote the differentiation of Th2 cells in lymph nodes; and that promote T cell help for the induction of the immunoglobulin isotypes IgG1 and IgE associated with allergy.

Selected Publications

• Mohrs K, AE Wakil, N Killeen, RM Locksley, M Mohrs.  2005.  A two-step process for cytokine production revealed by IL-4 dual-reporter mice.   Immunity 23:419-29.
• Veldhoen M, RJ Hocking, CJ Atkins, RM Locksley, B Stockinger. 2006.  TGF- B in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.   Immunity 24:179-89.
• Scheu S, DB Stetson, RL Reinhardt, JH Leber, M Mohrs, RM Locksley.  2006.  Activation of the integrated stress response during T helper cell differentiation.   Nature Immunol 7:644-651.
• Voehringer D, TA Reese, X Huang, K Shinkai, RM Locksley.  2006.  Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system. J Exp Med 203:1435-1446.
• Scheu S, DB Stetson, RL Reinhardt, *JH Leber, M Mohrs, RM Locksley. 2006. Activation of the integrated stress response during T helper cell differentiation. Nature Immunol 7:644-651.
• Reese TA, H-E Liang, AM Tager, AD Luster, N van Rooijen, D Voehringer, RM Locksley. 2007. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 447:92-96.
• Reinhardt RL, H-E Liang, RM Locksley. 2009. Cytokine-secreting follicular T cells shape the antibody repertoire. Nature Immunol 10:385-93.
• Sullivan BM, RM Locksley. 2009. Basophils: a nonredundant contributor to host immunity. Immunity 30:12-20.
• Seibold MA, *TA Reese, S Choudhry, MT Salam, K Beckman, C Egn, A Atakilit, K Meade, M Lenoir, HG Watson, S Thyne, R Kumar, KB Weiss, LC Grammar, P Avila, RP Schleimer, JV Fahy, J Rodriguez-Santana, W Rodriguez-Cintron, RG Boot, D Sheppard, FD Gilliland, RM Locksley, EG Burchard. 2009. Differential enzymatic activity of common haplotypic versions of the human acidic mammalian chitinase protein. J Biol Chem (in press).

Ma, Averil

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Research Interests

The proper regulation of immune signals is critical for preventing autoimmune diseases such as inflammatory bowel disease. Our laboratory’s interest in this area has focused on the intracellular mechanisms by which immune signals such as TNF- and TLR-induced signal transduction events are regulated. By targeting the A20 gene in mice, we found that a A20 is essential for restricting TNF, TLR and NOD induced activation signals in macrophages and dendritic cells (Lee et al, Science 2000, Boone et al, Nature Immunology 2004; Turer et al, J Exp Med 2008; Hitotsumatsu et al, Immunity 2008). We have further found that A20 is a unique ubiquitin modifying enzyme that regulates both the activity and stability of signaling proteins such as RIP and TRAF6 (Wertz et al, Nature 2004; Boone et al, Nature Immunology 2004). A20 appears to work with other ubiquitin dependent proteins, such as ABIN-1, and ABIN-1 deficiency is independently critical for regulating TNF signals (Oshima et al, Nature 2009).

In addition to being biologically and biochemically potent molecules, these proteins are extraordinarily important for human diseases. Recent genetic studies suggest that A20 and ABIN-1 are important for regulating multiple autoimmune diseases in human patients (e.g., Musone et al, Nature Genetics 2008). In addition, loss of A20 function is pathogenetic in a large percentage of human B cell malignancies. Ongoing studies focus on the mechanisms by which A20, ABIN-1, and related proteins function, on the cell signaling cascades and cellular functions impacted by these proteins, and on the roles of the roles of these ubiquitin dependent proteins in regulating immune responses and autoimmunity.

Selected Publications

• Lee EG, Boone DL, Chai S, Libby S, Chien M, Lodolce JP, and Ma A. 2000. Failure to regulate TNF induced NF-kB and cell death responses in A20 deficient mice. Science 289;2350-54.
• Ma A. 2007. T-bet sends host-microbe mutualism awry. Cell 131;33-35.
• Oshima S, Turer EE, Callahan JA, Advincula R, Chai S, Barrera J, Shifrin N, Lee B, Woo T, Malynn BA, and Ma A. 2009. ABIN-1 is a ubiquitin sensor that restricts TNF induced cell death and sustains embryonic development. Nature 457;906-910.
• Malynn BA and Ma A. 2009. A20 takes on tumors: tumor suppression by a ubiquitin editing enzyme. Journal of Experimental Medicine 206;977-980.
• Mortier E, Advincula R, Kim L, Chmura S, Barrera J, Reizis B, Malynn BA, and Ma A. Macrophage and dendritic cell derived IL-15Ra support distinct CD8+ T cell subsets. Immunity (in press).

Phillips, Kathryn

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Research Interests

Dr. Phillips’ research focuses on how health care is organized, delivered, and financed in the US. She focuses on personalized medicine – specifically, targeting health care interventions to patients based on their genetics – and the impact of personalized medicine on clinical care, health economics, and health policy, particularly in the area of cancer screening and treatment. ??Dr. Phillips conducts cross-disciplinary research across the basic, clinical, and social sciences and also across academia, industry, and government. She is serving as the Prinicipal Investigator on several NIH and foundation grants, has led or participated in approximately 35 funded research grants, and has had continuous funding from the NIH throughout her career.

Selected Publications

• Phillips KA, Van Bebber S, Liang SY, and the CANPERS Research Group. Challenges to the translation of personalized medicine: Utilization, preferences, and economic value (in press,   Current Opinions in Molecular Therapeutics)
• Van Bebber SL, Liang SY, Phillips KA, Marshall D, Johnson FR, Walsh JW, Kulin N. Valuing risk information: Willingness to pay for genetic testing for colorectal cancer risk. Personalized Medicine 2007, 4(3): 342-350.
• Marshall D, Johnson FR, Phillips KA, Marshall JK, Thabane L, Ozdemir S, Kulin N. Measuring preferences for colorectal cancer screening using choice-format stated preferences. Value in Health 2007, 10(5): 415-430.
• Haas J, Phillips KA, Fitzmaurice G, Brawarsky P, Liang SY, Klabunde CN, Brown ML. Association of regional variation in physicians' colorectal cancer screening recommendations with individual use of colorectal cancer screening. Preventing Chronic Diseases 2007, 4(4): www.cdc.gov/pcd.

Tempero, Margaret

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Research Interests

The Pancreas Cancer Program is comprised of a multi-disciplinary group of investigators focused on pancreatic cancer. These investigators include a team of clinicians and clinical scientists in endocrinology, epidemiology, gastroenterology, medical oncology, radiation oncology and surgical oncology who are qualified to address critical issues in pancreatic cancer, with full integration of faculty in basic and population sciences. The investigators in the program are not only interested in identifying better treatments but also in identifying persons at high risk for the disease and methods for screening and prevention.

Selected Publications

• Hruban RH, Rustgi AK, Brentnall TA, Tempero MA, Wright CV, Tuveson DA. Pancreatic Cancer in Mice and Man: The Penn Workshop 2004. Cancer Res 66:(1): 14-7), January 2006.
• Ko AH, Dito E, Schillinger B, Venook AP, Bergsland EK, Tempero MA. Phase II study of fixed dose rate gemcitabine with cisplatin for metastatic adenocarcinoma of the pancreas. J Clin Oncol, January 2006.
• Jhawer M, Rosen L, Dancey J, Hochster H, Hamburg S, Tempero MA, Clendeninn N, Mani S. Phase II Trial of Nolatrexed Dihydrochloride [Thymitaq, AG 337] in Patients with Advanced Hepatocellular Carcinoma. Invest New Drugs, June 2006.

Terdiman, Jonathan P

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Research Interests

I perform clinical and translation research in the areas of colorectal cancer prevention, especially among individuals at high risk for cancer, such as those with hereditary cancer syndromes or those with longstanding inflammatory bowel disease. Particular areas of interest include the optimal provision of genetic counseling and testing, cancer risk factor identification and risk mitigation by interventions such as drugs (chemoprevention) and colonoscopy. I also study the use of genetic and genomic markers to determine cancer risk and prognosis and prediction of response to therapy among those already diagnosed with cancer. I also am interested in projects related to biomarkers of prognosis and prediction of response to therapies in patients with inflammatory bowel disease. My research is performed in collaboration with basic science investigators in the UCSF Cancer Center (Fred Waldman, MD, PhD), UCSF Center for Colitis and Crohn’s Disease (Averil Ma, MD), and investigators at outside institutions including the Division of Research of Kaiser Permanente-northern California, the Dana Farber and MD Anderson Cancer Center, the Mayo Clinic in Rochester, MN and others.

Selected Publications

• Shergill AK, Terdiman JP. Refining colorectal cancer screening recommendations based on gender. Gastroenterology 2007;132:2605-6.
• Terdiman JP. Hereditary diffuse gastric cancer: surveillance endoscopy is not enough to save lives. Gastroenterology 2007;133:1730-2.
• Shergill AK, Terdiman JP. Controversies in the treatment of Crohn's disease: The case for an accelerated step-up treatment approach. World J Gastroenterol 2008;14:2670-77.
• Li D, Terdiman JP. “Did you check my colon for flat polyps?" Should patients and colonoscopists really be concerned? Gastroenterology. 2008.
• Shergill AK, Terdiman JP. The Early Use of Immunosuppression Reduces Morbidity in Patients with Moderately Severe or Severe Crohn's Disease. Gastroenterology, 2008;135:1417-20.
• Nguyen SP, Bent S, Chen YH, Terdiman JP. Gender as a risk factor for advanced neoplasia and colorectal cancer: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2009 Jun;7(6):676-81.
• Wang JY, Terdiman JP, Vittinghoff E, Minichiello T, Varma MG. Hospitalized ulcerative colitis patients have an elevated risk of thromboembolic events. World J Gastroenterol. 2009 Feb 28;15(8):927-35.
• Li D, Jin C, McCulloch C, Kakar S, Berger BM, Imperiale TF, Terdiman JP. Association of Large Serrated Polyps With Synchronous Advanced Colorectal Neoplasia. Am J Gastroenterol. 2009;104:695-702.

Weiss, Arthur

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Research Interests

The response of T lymphocytes to antigen presents a unique opportunity to study how complex molecular interactions between cells can lead to cell differentiation and proliferation. We are interested in understanding how T and B cell receptors involved in antigen recognition initiate signal transduction events that regulate cell responses. We know that such receptors functionally interact with tyrosine kinases and phosphatases, enzymes that regulate protein phosphorylation, to induce signaling pathways that regulate gene expression. By studying the mechanisms by which these molecules are regulated and how they control cellular responses in development, we hope to understand how signaling pathways in normal immune responses and how perturbations in these pathways can lead to immune deficiency or autoimmunity.

Selected Publications

• Roose J, M Mollenauer, M Ho, T Kurosaki, A Weiss. Unusual interplay of two types of Ras activators, RasGRP and SOS, establishes sensitive and robust Ras activation in lymphocytes. Mol Cell Biol 27 2007:2732-2745.
• Deindl S, TA Kadlecek, T Brdicka, X Cao, A Weiss, J Kuriyan. Structural basis for the inhibition of tyrosine kinase activity of ZAP-70. Cell 129 2007:735-746.
• Zhu JW, T Brdicka, TR Katsumoto, J Lin, A Weiss. Structurally distinct phosphatases CD45 and CD148 regulate B cell and macrophage immunoreceptor signaling. Immunity 28 2008:183-196.
• Levin SE, C Zhang, TA Kadlecek, K Shokat, A Weiss, A. Inhibition of ZAP-70 kinase activity via an analog-sensitive allele blocks T cell receptor and CD28 superagonist signaling. J Biol Chem 283 2008:15419-15430.

HEPATOLOGY TRAINING GRANT

Baron, Jody

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Research Interests

The Baron research group studies mechanisms involved in the immunopathogenesis of hepatitis B-related liver disease as well as the basic principles of innate and adaptive immunity to viral pathogens in general. Work relevant to hepatitis B is based on the observation that liver disease in HBV-infected individuals is immunemediated rather than cytopathic. Because natural hepadnaviral infections occur only in humans and other species whose immune systems vary from individual to individual (outbreeding), it is difficult to study immunopathogenesis in these hosts. To circumvent this limitation, the lab developed a novel transgenic mouse system that models the immune response to hepatitis B that would occur in the setting of natural infection. This mouse model has the potential to elucidate the basic mechanisms involved in immunopathogenesis of acute and chronic hepatitis B infection. In addition, the model holds promise for illuminating the fundamental aspects of innate and adaptive immunity to viral pathogens. Experiments are designed to use and extend the model to identify the mechanisms involved in acute and chronic hepatitis with the long-term goal of developing a comprehensive understanding of the role of innate and adaptive immunity in HBV clearance and virus-induced liver damage. Initial work uncovered a function for Natural Killer T lymphocytes (NKT cells), a population of innate-like lymphocytes whose role was previously unclear. More recently, the Baron group developed an agedependent mouse model of HBV infection in which young mice fail to clear HBV antigens, but adult mice exhibit a robust immune response, mimicking exactly the responses seen in humans. Data from the mouse model show that hepatic T follicular helper cells and IL-21 have an important role in determining the immune response to HBV. Future plans are to use the model to further understand the differences in the immune responses primed in the young mice as compared to the adult mice, and to identify the cellular and molecular mechanisms that underpin these different immune priming events and different disease outcomes. These studies will identify new potential therapeutic targets to treat HBV.

Selected Publications

• Baron JL, Gardiner L, Nishimura S, Locksley R, Ganem D. Activation of a non-classical NKT cell subset in a transgenic mouse model of hepatitis B virus infection. Immunity 2002;16:583-594.
• Matsuda JL, Gapin L, Baron JL, Sidobre S, Stetson DB, Mohrs M, Locksley RM, Kronenberg M. Mouse V alpha 14i natural killer T cells are resistant to cytokine polarization in vivo. Proc Natl Acad Sci U S A 2003;100:8395-400.
• Stetson DB, Mohrs M, Reinhardt RL, Baron JL, Wang ZE, Gapin L, Kronenberg M, Locksley RM. Constitutive Cytokine mRNAs Mark Natural Killer (NK) and NK T cells Poised for Rapid Effector Function. J Exp Med 2003;198:1069-1076.
• Villarinho S, Ogasawara K, Nishimura S, Lanier LL, Baron JL. Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to Hepatitis B Virus. Proc Natl Acad Sci USA, 2007;104 :18187-92.

Bull, Laura

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Research Interests

The goal of research in the Bull laboratory is to advance understanding of hereditary cholestatic diseases as well as determine the role of genetics in more complex cholestatic disorders. Several diseases are under study simultaneously, including progressive familial intrahepatic cholestasis (PFIC), familial hypercholanemia, Aaegenes syndrome and intrahepatic cholestasis of pregnancy (ICP). In the case of the first two diseases, Dr. Bull identified the genes responsible. Researchers in the Bull lab generated mice with a mutation in Atp8b1, a gene mutated in PFIC. These animals exhibit defective regulation of intestinal reabsorption of bile acids, and develop cholestasis when challenged with bile acids. Notably, the cholestatic phenotype depends upon strain background, enabling the lab to genetically map modifier loci affecting severity and manifestations of the Atp8b1-deficient phenotype. Studies to identify the genetic variation underlying these loci are underway. Studies of hypercholanemia in the Bull lab indicate that mutation in 2 (TJP2 and BAAT) or more genes is responsible, and that the disorder lies in a border zone between simple and complex genetic traits. For study of ICP, pregnant women with ICP, and matched controls, are being recruited from California and Santiago, Chile. Two approaches toward investigation of candidate ICP genes are being used: 1) sequencing of candidate genes to screen for enrichment of rare variants in cases, compared to controls, and 2) SNP genotyping studies to identify variants associated with ICP. Ancestry is being controlled for, as appropriate. Correlation of genetic findings with clinical and serum biochemical features will also be possible.

Selected Publications

• Knisely AS, Strautnieks SS, Meier Y, Stieger B, Byrne JA, Portmann BC, Bull LN, et al. Hepatocellular Carcinoma in ten children under five years old with bile salt export pump deficiency. Hepatology, 2006;44:478-486.
• Groen A, Kunne C, Paulusma CC, Kramer W, Agellon LB, Bull LN, Oude-Elferink RPJ. Intestinal bile salt absorption in Atp8b1 deficient mice. J Hepatol 2007;47:114-22.
• Strautnieks S, Byrne J, Pawlikowska L, Cebecauerov· D, Rayner A, Dutton L, Meier Y, et al. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology 2008;134:1203-1214.
• Hussaini H, Bassas A, Verkade H, Groen A, Kunne C, Jongsma G, van den Oever K, Petruzelli M, Vrins C, Bull L, Paulusma C, Oude-Elferink R. Enhanced biliary cholesterol output in Atp8b1 mutant mice is Abcg5/Abcg8-independent. Gut 2008, in press.

Fix, Oren

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Research Interests

Dr. Fix‟s research program is focused primarily on the clinical study of acute liver failure as the UCSF Principal Investigator of the NIH-funded multicenter Acute Liver Failure Study Group (ALFSG). The ALFSG has maintained an ongoing registry since 1998 that involves the prospective collection of clinical and epidemiological data and tissue in subjects with acute liver injury or acute liver failure. The data and tissue are used to analyze trends, develop prognostic information and provide materials to investigators in this field. UCSF has consistently been one of the top enrolling sites and was chosen to remain a key part of the group during its recent application for refunding in a competitive process that reduced the number of sites from 23 to 13. Dr. Fix was awarded the top enrolling site in 2010 for both acute liver injury and acute liver failure subjects and he maintains a strong and active presence in the group‟s Steering Committee, Ancillary Studies Committee, and Intensive Care Committee. The ALFSG completed a randomized clinical trial of Nacetylcysteine (NAC) in patients with non-acetaminophen-related acute liver failure and demonstrated that there is a survival benefit when patients who present with early (grade I or II) encephalopathy are treated with NAC compared to placebo. The group is in the planning stages of a Phase 2 trial of a novel drug in development that lowers serum ammonia levels and is hypothesized to improve encephalopathy and reduce the risk of intracranial hypertension and cerebral herniation in patients with acute liver failure. Dr. Fix is developing a checklist for intensive care management of acute liver failure that will be piloted among the ALFSG sites in the coming months. In addition to acute liver failure, Dr. Fix has a research interest in liver transplant-related cardiopulmonary complications of chronic liver disease, including portopulmonary hypertension, hepatopulmonary syndrome, and iron overload.

Selected Publications

• Fix OK, Peters MG, Davern TJ. Eosinophilic hepatitis caused by lamotrigine. Clin Gastroenterol Hepatol. 2006 Apr;4(4):xxvi. PubMed PMID: 16616339.
• Fix OK, Bass NM, De Marco T, Merriman RB. Long-term follow-up of portopulmonary hypertension: effect of treatment with epoprostenol. Liver Transpl. 2007 Jun;13(6):875-85. PubMed PMID: 17539008.
• Mukhtar NA, Fix OK. Portopulmonary Hypertension. J Clin Gastroenterol. 2011 Feb 15. [Epub ahead of print] PubMed PMID: 21325952.

Khalili, Mandana

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Research Interests

Dr. Khalili‟s patient-oriented research primarily involves on viral hepatitis and includes both clinical and translational components. Her research focuses on the underserved and ethnically diverse population and includes natural history studies of patients with hepatitis C, evaluation of mechanisms of glucose intolerance in patients with hepatitis C, evaluation of hepatocellular screening practices and outcomes in patients with hepatitis B, and drug therapies in patients with hepatitis C including specific racial populations such as African Americans and Latinos. In addition, she has conducted several multicenter treatment trials of patients with hepatitis B and C. To better define host factors associated with HCV disease progression and response to antiviral therapy, she is currently evaluating the relationship between HCV and diabetes while accounting for all major pathophysiologic mechanisms of glucose intolerance using state of art and novel techniques. Type 2 diabetes and insulin resistance is now considered an extrahepatic manifestation of HCV infection leading to liver disease progression and resulting in a decrease HCV response to anti-viral therapy. Her current focus is on the especially at-risk Latino population. Moreover, through a large NIH-funded Hepatitis B Research Network where she currently serves as one of the PIs, she is evaluating the natural history and optimal therapies in North American patients with chronic hepatitis B. She has formal training in research mentoring and involved in the Clinical and Translational Science Institute (CTSI)-Mentor Development Program. She also currently serves as the Director of the Mentor Consultation Unit addressing mentee and mentor issues and challenges related to research.

Selected Publications

• Khalili M, Vardanian AJ, Hamerski CM, Wang R, Bacchetti P, Roberts JP, Terrault NA. Management of hepatitis C-infected liver transplant recipients at large North American centres: changes in recent years. Clin Transplant. 2006 Jan-Feb;20(1):1-9. PubMed PMID: 16556146.
• Terrault N, Khalili M. A glimpse of future hepatitis C virus treatment paradigms. Hepatology. 2010 Feb;51(2):707-10. PubMed PMID: 20104511.
• Lam KD, Bacchetti P, Abbasi F, Ayala CE, Loeb SM, Shah V, Wen MJ, Reaven GM, Maher JJ, Khalili M. Comparison of surrogate and direct measurement of insulin resistance in chronic hepatitis C virus infection: impact of obesity and ethnicity. Hepatology. 2010 Jul;52(1):38-46. PubMed PMID: 20578127.

Lanier, Lewis

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Research Interests

The Lanier lab studies membrane receptors on human and mouse leukocytes that activate or inhibit cell proliferation and clonal expansion, cytokine production and cell-mediated cytotoxicity. The overall goal of the research is to understand the role of these receptors in immune defense against tumors and microbial pathogens, and explore their potential detrimental role in autoimmune diseases. The group focuses primarily on receptors expressed by Natural Killer (NK) cells; they are particularly interested in the activating NK receptors that signal by associating with two distinct signaling adapter proteins named DAP10 and DAP12. The DAP10 signaling adapter associates with the NKG2D receptor on NK cells and T cells, and initiates signaling through the PI3-kinase pathway. Researchers in the lab have implicated the NKG2D-DAP10 receptor in NK cell and T cell-mediated immune responses that are critical for combating certain tumors and viruses. The lab has also demonstrated a detrimental role for this receptor, however, in autoimmune diseases such as type I diabetes. The DAP12 signaling adapter associates with many different human and mouse receptors, including activating KIR, Ly49, CD94/NKG2C, and several myeloid receptors. Like the CD3 subunits of the T cell antigen receptor, DAP12 has an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. When a DAP12-associated receptor encounters its ligand, DAP12 is phosphorylated on tyrosine, which results in the recruitment and activation of the tyrosine kinases ZAP70 or syk and in turn initiates cytokine production and cell-mediated cytotoxicity. DAP12-associated receptors, such as Ly49H and Ly49P, are involved in immunity against cytomegalovirus infection.

Selected Publications

• Vilarinho S, K Ogasawara, S Nishimura, LL Lanier, JL Baron. Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to hepatitis B virus. Proc Natl Acad Sci USA, 2007;104:18187-18192.
• Lanier LL. Evolutionary struggles between NK cells and viruses. Nat Rev Immunol 2008;8:259-268.
• Rosen DB, W Cao, DT Avery, SG Tangye, Y-J Liu, JP Houchins, LL Lanier. Expression and function of LLT1, a ligand of human NKR-P1A, on activated B cells and dendritic cells. J Immunol 2008;180:6508-6517.
• Sun JC, LL Lanier. Tolerance of NK cells encountering their viral ligand during development. J Exp Med, 2008, In press.

Maher, Jacquelyn

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Research Interests

The Maher laboratory focuses on general mechanisms of liver injury as well as specific mechanisms of liver damage in the context of hepatic steatosis. General studies address cell death pathways in the liver (apoptosis/necrosis) and their connection to downstream events including inflammation and fibrosis. Research on fatty liver disease is directed toward identification of the factor(s) that trigger hepatocyte injury. Part of the work involves cell culture approaches, in which fatty acids are added to hepatocytes to explore the cellular signaling process that result in cell death (“lipotoxicity”). The precise mechanism of fatty acid-induced cell death is currently uncertain. Fatty acids activate several potentially lethal processes, such as activation of JNK and impairment of autophagy. Animal models are also used to examine the pathophysiology of fatty liver disease in vivo. These experiments focus on the identification of dietary macronutrients that have the greatest potential to provoke liver injury. Studies from the laboratory show that dietary sugar is particularly toxic to the liver, with a high potential to cause hepatocyte injury because of its conversion to toxic saturated fatty acids. Ongoing studies are addressing the disease-producing potential of various macronutrient combinations, such as one would encounter in a normal human diet. Hepatic lipid metabolism is monitored in vivo using stable isotopes as metabolic tracers.

Selected Publications

• Maher JJ, Leon P, Ryan JC. Beyond insulin resistance: Innate immunity in nonalcoholic steatohepatitis. Hepatology. 2008 Aug;48(2):670-8. Review. PubMed PMID: 18666225.
• Lam KD, Bacchetti P, Abbasi F, Ayala CE, Loeb SM, Shah V, Wen MJ, Reaven GM, Maher JJ, Khalili M. Comparison of surrogate and direct measurement of insulin resistance in chronic hepatitis C virus infection: impact of obesity and ethnicity. Hepatology. 2010 Jul;52(1):38-46. PubMed PMID: 20578127.

Monto, Alexander

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Research Interests

Dr. Monto's research addresses several aspects of hepatitis C virus (HCV) infection. As a hepatologist, he provides the clinical and liver disease-associated insights into HCV pathogenesis in several projects. He and collaborators have particularly focused on immunological studies into the roles of CD14+ monocytes and natural killer (NK) cells in disease due to hepatitis C. Collaborations with Dr. Lynn Pulliam have found that monocytes have a specific abnormal phenotype in the setting of chronic HCV that implies that they traffic into the brain as well as into the liver. Monocytes from HIV/HCV coinfected individuals have increased expression of a significant number of genes associated with chemotaxis and inflammation in both HIV and HCV monoinfections. They have also shown that soluble products from monocytes of individuals with HCV or HIV/HCV cause neural cell death and apoptosis in human brain cultures. In collaboration with Dr. James Ryan on the study of NK cells in patients with prior HCV exposure, specific Killer Inhibitory Receptor (KIR)/HLA pairs have been found to be associated with significantly higher rates of spontaneous HCV clearance. Recently he has also published several manuscripts on clinical aspects of the management of hepatocellular carcinoma (HCC). These include the fact that patients with non-cirrhotic liver disease from HCV are still at risk for HCC; that implementation of a multidisciplinary HCC treatment team can lead to improved clinical outcomes; and that hepatic arterial embolization of HCC‟s can be safely performed even in patients with some decompensation of their cirrhosis (Child-Pugh Class B).

Selected Publications

• Currie SL, Ryan JC, Tracy D, Wright TL, George S, McQuaid R, Kim M, Shen H, Monto A. A prospective study to examine persistent HCV reinfection in injection drug users who have previously cleared the virus. Drug Alcohol Depend 2008;93:148-154.
• Shah T, Lampiris H, Vu M, Monto A, Tien PC. Resolution of hepatitis C virus-induced steatosis improves tolerability of antiretroviral drugs associated with hepatotoxicity in an HIV-infected individual. J Infect Dis 2008;197:932-933.
• Bonkovsky HL, Tice AD, Yapp RG, Bodenheimer HC, Monto A, Rossi SJ, Sulkowski MS. Efficacy and safety of peginterferon alfa-2a/ribavirin in methadone maintenance patients: randomized comparison of direct observed therapy and self-administration. American Journal of Gastroenterology 2008;103:2757-2765.
• Sewell JL, Stick KM, Monto A. Hepatocellular carcinoma after sustained virologic response in hepatitis C patients without cirrhosis on a pre-treatment liver biopsy. Eur J Gastroenterol Hepatol. 2009;21:225-229.
• Garcia-Tsao G, Lim J, Monto A, Yee H, Durfee J, Dieperink E, Dominitz J, Ross D, Valdiserri R. Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program. American Journal of Gastroenterology 2009;104:1802-1829.

Peters, Marion

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Research Interests

Dr. Peters pursues clinical/translational studies of liver disease due to hepatitis B and C infection. Her group is particularly interested in viral hepatitis in complicated clinical settings, such as in patients with co-morbid conditions including alcoholism or HIV infection. In these complex situations the group focuses on immunology of the liver; they study the role of host responses to hepatitis virus infection, and examine the effect of alcohol or HIV on the progression of viral hepatitis and the response to anti-viral therapy. The Peters group also addresses fundamental host-viral interactions in hepatitis C and hepatitis B infection. Specifically, they explore the role of inflammatory cytokines and their receptors in the pathogenesis of hepatitis using DNA polymorphism analysis and mRNA gene profiling. They study the factors associated with progression of hepatitis C and HIV, including race/ethnicity, immune status and the role of reproductive aging. They are studying the role of noninvasive markers of fibrosis on outcome of liver disease in HIV-HCV co-infected individuals in a large multicenter NIH funded study, the Women's Interagency HIV study (WIHS). Clinical studies by Dr. Peters assess the outcome of hepatitis B and C in alcoholic or HIV-infected patients as well as the impact of these co-morbid illnesses on their response to therapy. Additional studies examine bone density in patients with chronic liver disease and after liver transplantation. Finally, Dr. Peters is investigating the effect of age on presentation of autoimmune liver disease and the factors affecting recurrence of autoimmune liver diseases after liver transplantation.

Selected Publications

• Julie H. Ishida, Marion G. Peters, Chengshi Jin, Karly Louie, Vivian Tan, Peter Bacchetti, Norah A. Terrault. Influence of Cannabis Use on Severity of Hepatitis C Disease. Clin Gastroenterol Hepatol 2008:6(1):69-75
• Margaret Koziel and Marion Peters. Viral Hepatitis in HIV Infection. New Eng J Med, 2007: 356; 1445-54.
• David J. Quan and Marion G. Peters. Tenofovir disoproxil fumarate for the treatment of hepatitis B virus infection: pharmacokinetics and clinical efficacy. Therapy 2007; 4; 141-151.
• Marion Peters. Hepatobiliary Complications. American Academy of HIV Medicine Study Guide, Fundamentals of HIV Medicine 2007. John Stansell Editor. In press 2008.
• Oren K Fix, Stephen A. Locarnini and Marion G. Peters. Virology and clinical management of Heptitis B and HIV co-infection. PRN notebook 2007 in press
• George Lau, Patrick Marcellin and Marion Peters. Chronic hepatitis B – a global health problem requiring coherent worldwide treatment strategies. Hepatology International In press 2007.
• Marion Peters: HIV and Hepatitis B Virus Coinfection, Top HIV Med. 2007;15:163-6.
• Peters MG. Special populations with hepatitis B virus infection. Hepatology. 2009 May;49(5 Suppl):S146-55.

Ryan, James

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Research Interests

Dr. Ryan‟s research has focused on innate immunity in rodents and in humans. He has authored seminal discoveries in the field of innate immunity, including the cloning and functional characterization of the canonical NK cell receptor, NK1.1, and members of the Ly49 and KIR family of NK cell receptors. He described the first genetic complex of NK cell receptors, the NKC on mouse chromosome 6 and human chromosome 12. He identified specific molecular pathways of receptor-mediated NK cell activation and inhibition, including a requirement for tyrosine phosphatases in NK cell inhibitory signaling. He described early genetic evidence predicting the existence activating NK cell receptors, and he has identified these using a compendium of complementation expression cloning techniques. He is the co-discoverer of MDL-1, a lectin like receptor for Dengue Virus on macrophages that triggers cytokine storm in Hemorrhaging Fever, and cloned TREM2, a receptor controlling macrophage polarization, and the anchor gene of the TREM Receptor Cluster (TRC) on human chromosome 6. In recent years, Dr. Ryan has changed his research emphasis to the fundamental roles of innate immunity in infectious and inflammatory liver diseases. In collaboration with Dr. Mary Carrington at the NCI and with Lewis Lanier, Mike McCune, Norah Terrault and others at the UCSF Liver Center, he has recently embarked upon a comprehensive analysis of polymorphisms in NK cell receptors as they correlate with divergent clinical outcomes of HCV. He also investigates the role of macrophage polarization states as they relate to the pathogenesis of steatohepatitis due to obesity or due to ethanol toxicity. These latter investigations involve collaborations with Jacqueline Maher, Nathan Bass, and Jody Baron at the Liver Center and entail current or anticipated utilization of the Liver Center Flow Cytometry, Immunohistochemistry, and Pathology cores.

Selected Publications

• Ryan JC, Morey JS, Bottein MY, Ramsdell JS, Van Dolah FM. Gene expression profiling in brain of mice exposed to the marine neurotoxin ciguatoxin reveals an acute anti-inflammatory, neuroprotective response. BMC Neurosci. 2010 Aug 26;11:107.
• Ryan JC, Cross CA, Van Dolah FM. Effects of COX inhibitors on neurodegeneration and survival in mice exposed to the marine neurotoxin domoic acid. Neurosci Lett. 2011 Jan 3;487(1):83-7.
• Shegarfi H, Dai KZ, Inngjerdingen M, Ryan JC, Vaage JT, Rolstad B, Naper C. The activating rat Ly49s5 receptor responds to increased levels of MHC class Ib molecules on Listeria monocytogenes-infected enteric epithelial cells. Eur J Immunol. 2010 Dec;40(12):3535-43.
• Shegarfi H, Dai KZ, Daws MR, Ryan JC, Vaage JT, Rolstad B, Naper C. The rat NK cell receptors Ly49s4 and Ly49i4 recognize nonclassical MHC-I molecules on Listeria monocytogenes-infected macrophages. J Leukoc Biol. 2011 Apr;89(4):617-23.

Stainier, Didier

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Research Interests

The goals of the Stainier laboratory are to understand the formation, function and homeostasis of organs during vertebrate development. They are interested in understanding the cellular and molecular events that underlie cellular differentiation, tissue morphogenesis and organ function during the formation of the cardiovascular system (the heart and the blood vessels) as well as the liver and pancreas. Their initial approach consists of screening for mutations that affect these processes in zebrafish, a vertebrate model system that allows forward genetics as well as embryological studies. This forward genetic approach leads to the isolation of genes critical for these processes, and together with complementary methods allows us to assemble underlying molecular pathways. They also aim to understand how these genes control the behavior of the cells that form these complex three-dimensional structures, and the zebrafish allows one to study cell behavior in real time and in the context of the living embryo. Ultimately, They would like to reach a systems level understanding of these processes. And, as the work progresses, they also hope to contribute to the understanding of how defects in the processes they are studying lead to human congenital disease or malformations, or even to predisposition to disease. In terms of their liver work, the Stainier laboratory completed a detailed analysis of wild-type liver development in zebrafish, conducted large-scale forward genetic screens for genes regulating liver development including hepatocyte differentiation, analyzed the role of Fgf, Bmp and Wnt signaling in hepatic induction, developed methods to ablate at will specific lineages including hepatocytes, and began to analyze the role of endothelial cells during liver formation.

Selected Publications

• Ober EA, Verkade H, Field HA, Stainier DY. Mesodermal Wnt2b signalling positive regulates liver specification. Nature 2006;442:688-691.
• Shin D, Shin CH, Tucker J, Ober EA, Rentzsch F, Poss KD, Hammerschmidt M, Mullins MC, Stainier DY. Bmp and Fgf signaling are essential for liver specification in zebrafish. Development 2007;134:2041-2050.
• Dong PD, Munson CA, Norton W, Crosnier C, Pan X, Gong Z, Neumann CJ, Stainier DY. Fgf10 regulates hepatopancreatic ductal system patterning and differentiation. Nat Genet 2007;39:397-402.
• Schlegel A, Stainier DY. Microsomal triglyceride transfer protein is required for yolk lipid utilization and bsorption of dietary lipids in zebrafish larvae. Biochemistry 2006;45:15179-15187.
• Chung, W-S., Shin, C.H. and Stainier D.Y.R. Bmp2 signaling regulates the hepatic vs pancreatic fate decision. Developmental Cell 2008;15: 738-748.
• Sakaguchi, T.F., Sadler, K.C., Crosnier, C. and Stainier, D.Y.R. Endothelial signals modulate hepatocyte apico-basal polarization in zebrafish. Current Biology 2008;18: 1565-1571.

Terrault, Norah

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Research Interests

Dr. Terrault's patient-oriented research program focuses on defining the natural history and predictors of disease outcomes in patients with chronic viral hepatitis, and evaluating treatment strategies to prevent cirrhosis and improve long-term survival. Patients with cirrhosis and liver transplant recipients are the primary populations of interest. The UCSF Transplant Program is an important resource for her research with 2500 transplants performed since the program began in 1989. Current studies include the evaluation of the effect of donor factors on hepatitis C virus (HCV) disease recurrence, gender and racial-ethnic disparities in HCV disease outcomes, safety and efficacy of antiviral therapy in preventing recurrent HCV infection, and identifying factors influencing outcomes of HCV-HIV coinfected liver transplant recipients. Previous studies by Dr. Terrault have defined the outcomes of HIV-infected transplant recipients with hepatitis B virus (HBV) infection, the importance of hepatitis B immunoglobulin in prevention of HBV recurrence, and the role of occult HBV infection as a risk for recurrent disease post-transplantation. Additionally, she has been actively engaged in clinical/translational research in viral hepatitis in the non-transplant setting with past and current NIH-funded programs including the NIH-NIDDK Virahep-C Study, evaluating the efficacy of HCV treatment in African- Americans, the NIH/NIAID sponsored Bay Area Hepatitis C Cooperative Research Center determining immunologic factors associated with non-response to HCV treatment, and the NIH/NIDDK Hepatitis B Clinical Research Network studying the natural history and optimal treatment of chronic HBV. Over the past 10 years, through these consortium activities as well as other CDC and NIH-sponsored studies, she has established large population-based cohorts of patients with chronic viral hepatitis. These, together with the UCSF Hepatology clinical practice, serves as an ongoing resource for patient-oriented research including a clinical trials program, focused on new therapies for chronic HCV and HBV and provide an important avenue for collaborative clinical and translational research related to drug development.

Selected Publications

Terrault N, Khalili M. A glimpse of future hepatitis C virus treatment paradigms. Hepatology. 2010 Feb;51(2):707-10. PubMed PMID: 20104511.

Willenbring, Holger

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Research Interests

Complex differentiation and facultative regenerative abilities are hallmarks of hepatocytes, the cells of the liver that provide its manifold functions. Hepatocytes derive from liver progenitors, which expand and commit to one of two possible cell fates during late embryonic development and, in response to chronic injuries, also during adult liver regeneration. Dr. Willenbring aims to obtain a detailed understanding of these differentiation processes, which he believes is essential for their in vitro recapitulation in cells intended for transplantation. In particular, the Willenbring lab is working on identifying essential regulators of the hepatocyte differentiation program in order to direct the functional differentiation of immature cells from abundant cell sources such as embryonic and induced pluripotent stem cells, which could then be used for therapy of human diseases impairing hepatocyte function. In addition, this knowledge may provide novel means to directly restore the function or unlock the regenerative capabilities of ailing hepatocytes. For example, inhibitors or mimics of microRNAs that we have identified as regulators of key functions of hepatocytes can be used to modulate these functions in vivo. Since hepatocyte progenitor cell characteristics could explain why liver cancers are refractory to therapy, his group is furthermore interested in identifying and isolating the cells that give rise to liver cancer. The lab is tracking the emergence and development of liver cancer-initiating cells in vivo to determine the molecular mechanisms that drive liver cancer formation. By obtaining an improved understanding of the biology of liver cancer initiation, Dr. Willenbring hopes to contribute to the development of strategies for early detection and effective eradication of liver cancer. Similarly, he is committed to translating the results of his work on liver cell therapy and regeneration into therapeutic options for patients with severe liver diseases.

Selected Publications

• Terrault NA. Benefits and risks of combination therapy for hepatitis B. Hepatology. 2009 May;49(5 Suppl):S122-8.
• Terrault NA, Im K, Boylan R, Bacchetti P, Kleiner DE, Fontana RJ, Hoofnagle JH, Belle SH; VIRAHEP- C Study Group. Fibrosis progression in African Americans and Caucasian Americans with chronic hepatitis C. Clin Gastroenterol Hepatol. 2008 Dec;6(12):1403-11.
• Terrault NA. Hepatitis C therapy before and after liver transplantation. Liver Transpl. 2008 Oct;14 Suppl 2:S58-66.