Training Grant Faculty Research Interests

GI TRAINING GRANT

We seek to discover the mechanisms that switch inflammation and pain on and off through studies at the molecular, cellular and organismal level. An understanding of the mechanisms that initiate and terminate inflammation and pain will provide insights into new therapies for prevalent and debilitating human diseases. The major general question of our work is: "What are the mechanisms that initiate and terminate neurogenic inflammation and pain transmission?" Specific questions include: How do proteases signal to sensory neurons, sensitize transient receptor potential channels, and initiate neurogenic inflammation and hyperalgesia to thermal and mechanical stimuli? How do cell-surface and endosomal peptidases regulate the activity and trafficking of neuropeptide receptors? What are the mechanisms that target protease-activated receptors, neuropeptide receptors, and transient receptor potential ion channels to and from the plasma membrane?

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.

Research in my laboratory is aimed at understanding the mechanisms underlying the development of cholestasis, through study of patients and animal models. Currently, our studies are focused on the following: (1) characterization of the differences between FIC1 disease (due to mutation in ATP8B1) and B.S.EP disease (due to mutation in ABCB11), (2) identification of genetic factors underlying intrahepatic cholestasis of pregnancy and lymphedema-cholestasis syndrome, (3) identification of factors that may influence the phenotype of patients with FIC1 disease through genetic studies to identify loci that modify phenotypes in the Fic1 mutant mouse and (4) participation in the CLiC (Cholestatic Liver Disease in Children) consortium.

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.

Selected Publications

• Kubo A, Corley DA. Marked Multi-Ethnic Variation of Esophageal and Gastric Cardia Carcinomas within the United States. American Journal of Gastroenterology, 2004; 99(4):582-8
• Sharma P, McQuaid K, Dent J, Fennerty MB, Sampliner R, Spechler S, Cameron A, Corley D, Falk G, Goldblum J, Hunter J, Jankowski J, Lundell L, Reid B, Shaheen NJ, Sonnenberg A, Wang K, Weinstein W. 2004. A critical review of the diagnosis and management of Barrett's esophagus: the AGA Chicago Workshop. Gastroenterology 2004;127(1):310-330.
• Corley DA, Kubo A. The Influence of Classification on Cancer Incidence Rates: An Analysis of Gastric Cardia Carcinomas. JNCI (in press)

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

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.

• The impact of adherence on the cost-effectiveness of screening for colorectal cancer
• Socio-economic variation in patient-borne costs of cancer screening
• Evaluation of new techniques to decrease mortality from esophageal adenocarcinoma.

Selected Publications

• Somsouk M, Gralnek I, Inadomi JM. Management of obscure occult gastrointestinal bleeding: a cost-minimization analysis. Clinical Gastroenterology and Hepatology 2008;6:661-670.
• Rubenstein JH, Dahlkemper A, Kao JY, Zhang M, Morgenstern H, McMahon L, Inadomi JM. A Pilot study of the association of low plasma adiponectin and Barrett’s esophagus. American Journal of Gastroenterology 2008;103:1358-1364.
• Inadomi JM. Fear of loss, not promise of gain, drivees practice patterns in Barrett’s esophagus. Gastroenterology 2008;134:1258-1260.
• Rubenstein JH, Sonnenberg A, Davis J, McMahon L, Inadomi JM. Effect of a prior endoscopy on outcomes of esophageal adenocarcinoma among United States veterans. Gastrointestinal Endoscopy 2008; June 9: epub ahead of print.

One focus of research in my group is the adenovirus receptor CAR in epithelial malignancies. We have found that the adenovirus receptor CAR frequently exhibits reduced expression in gastrointestinal cancers, including liver cancer. Our goal is to elucidate the molecular mechanisms regulating CAR expression in cancer cells, towards designing novel combination therapies consisting of recombinant adenoviruses and signal transduction inhibitors that increase CAR expression. A second project focuses on the rational development of novel combination therapies for cancer based on the analysis of relevant cellular signal transduction pathways. We have applied this approach to improve the cytotoxicity of oncolytic adenoviruses by combining these agents with small molecule signal transduction inhibitors.

Selected Publications

• Korn WM, Maca 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.

Since my advancement in July 2005 to Associate Professor of Clinical Medicine, the major change in my clinical activities has been the launching of the Intestinal Rehabilitation Program. My outpatient and inpatient clinical activity continues to involve general gastroenterology and specialized consultation in motility and functional gastrointestinal disorders, as well as endoscopy.

Selected Publications

• Ladabaum U, McGonigle DJ, Roberts TP. Gastric Fundic Distension Activates Fronto- Limbic Structures but not Primary Somatosensory Cortex: A Functional Magnetic Resonance Imaging Study. Neuroimage 2007 Jan 15;34(2):724-32.
• Ladabaum U, When even people at high risk do not take up colorectal cancer screening. Gut 2007 Dec;56(12):1648-50
• Yen EF, Ladabaum U, Muthusamy VR, Cello JP, McQuaid KR, Shah JN, Colonoscopic Treatment of Acute Diverticular Hemorrhage Using Endoclips. Dig Dis Sci 2007 Dec 20
• Parekh M, Fendrick AM, Ladabaum U, As tests evolve and costs of cancer care rise: reappraising stool-based screening for colorectal neoplasia. Aliment Pharmacol Ther 2008 Apr;27(8):697-712

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 JC, LL Lanier. Tolerance of NK cells encountering their viral ligand during development. J Exp Med, 2008, In press.

mmunity to infection is mediated by T lymphocytes, specialized cells that use highly evolved recognition elements to maintain protection against foreign microbes. T lymphocytes differentiate from a naive state to an effector state. The latter is characterized by the ability to secrete large amounts of potent molecules, termed cytokines, that collectively orchestrate and focus the attack against pathogens. Different types of pathogenic organisms require different types of immune responses, that are defined by the spectrum of cytokines produced by the effector T lymphocytes. The most characterized effector subsets, termed type 1 and type 2 immunity, are associated with host defense against intracellular and intestinal pathogens, such as viruses and worms, respectively. In some cases, dysregulation of these type 1 and type 2 responses has been associated with tissue-destructive inflammatory disease, including autoimmune diseases, and allergy, respectively. My laboratory uses characterized challenges in inbred strains of mice to define genetic determinants that underlie the proclivity to form type 1 or type 2 responses. Understanding the underlying molecular mechanisms for the generation of these effector T lymphocytes may provide insights into the genetic susceptibility to infectious and autoimmune diseases.

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.

Our laboratory is interested in two general questions: 1) how innate immunity regulates immune responses to microbial pathogens; and 2) how memory T cells and NK cells are maintained in vivo. We are using a combination of gene targeting and biochemical approaches to answering these questions.

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, Yen B, Malynn BA, and Ma A. 2008. ABIN-1 is a ubiquitin sensor that restricts TNF induced cell death and sustains embryonic development. Nature (in press).

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.

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.

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, in press.

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

My research focuses on clinical and translational studies of portal hypertension, fatty liver disease, cholestatic liver disease and drug-induced liver disease. I am site director for the NIH-funded NASH Clinical Research Network, in which one local project addresses the genomic basis of nonalcoholic fatty liver disease. In concert with other multi-center groups, we are conducting therapeutic trials of pharmacological agents and blood products in chronic liver disease and portal hypertension. We are also testing novel therapies for acute liver failure.

Selected Publications

• Merriman RB, Ferrell LD, Patti MG, Weston SR, Pabst MS, Aouizerat BE, Bass NM. Correlation of paired liver biopsies in morbidly obese patients with suspected nonalcoholic fatty liver disease. Hepatology 2006t;44:874-880.
• Kadayifci A, Merriman RB, Bass NM. Medical treatment of non-alcoholic steatohepatitis. Clin Liver Dis 2007;11:119-140.
• Krasnoff JB, Painter PL, Wallace JP, Bass NM, Merriman RB. Health-related fitness and physical activity in patients with nonalcoholic fatty liver disease. Hepatology. 2008;47:1158-1166.
• Campos GM, Bambha K, Vittinghoff E, Rabl C, Posselt AM, Ciovica R, Tiwari U, Ferrell L, Pabst M, Bass NM, Merriman RB. A clinical scoring system for predicting nonalcoholic steatohepatitis in morbidly obese patients. Hepatology 2008;47:1916-1923.

My laboratory investigates tissue remodeling in liver injury. We have been focusing recently on oval cells, which are liver progenitor cells and proliferate in several forms of liver injury. Oval cells, can be isolated and, with expansion in culture, hold promise for cell-based therapy of a variety of liver diseases. We have recently defined a member of the TNF-alpha family of cytokines that appears to be a specific growth factor for a subset of oval cells. We are interested also in mechanisms of the fibrotic response to biliary injury. We have found that TGF? and the integrin ?v?6 have key roles.

Selected Publications

• Chang ML, Chen JC, Alonso CR, Kornblihtt AR, Bissell DM. Regulation of fibronectin splicing in sinusoidal endothelial cells from normal or injured liver. Proc Natl Acad Sci USA 2004;101:18093-98.
• Kikuchi S, Griffin CT, Wang SS, Bissell DM. Role of cd44 in epithelial wound repair: migration of rat hepatic stellate cells utilizes hyaluronic acid and cd44v6. J Biol Chem 2005;280:15398-404.
• Jakubowski A, Ambrose C, Parr M, Lincecum JM, Wang MZ, Zheng TS, Browning B, Michaelson JS, Baestcher M, Wang B, Bissell DM, Burkly LC. Tweak induces liver progenitor cell proliferation. J Clin Invest 2005;115:2330-40.
• Wang B, Dolinski B, Kikuchi N, Leone DR, Peters MG, Weinreb PH, Violette SM., Bissell DM. Role of ?v?6 in acute biliary fibrosis. Hepatology 2007;46:1404-12.

Research in my laboratory is aimed at understanding the mechanisms underlying the development of cholestasis, through study of patients and animal models. Currently, our studies are focused on the following: (1) characterization of the differences between FIC1 disease (due to mutation in ATP8B1) and B.S.EP disease (due to mutation in ABCB11), (2) identification of genetic factors underlying intrahepatic cholestasis of pregnancy and lymphedema-cholestasis syndrome, (3) identification of factors that may influence the phenotype of patients with FIC1 disease through genetic studies to identify loci that modify phenotypes in the Fic1 mutant mouse and (4) participation in the CLiC (Cholestatic Liver Disease in Children) consortium.

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.

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 JC, LL Lanier. Tolerance of NK cells encountering their viral ligand during development. J Exp Med, 2008, In press.

My laboratory studies basic mechanisms of hepatotoxicity, with a focus on clinically relevant diseases such as drug-induced liver injury and nonalcoholic steatohepatitis (NASH). One important goal is to identify hepatoprotective compounds that are therapeutic in the setting of acute liver failure or liver transplantation. In the setting of fatty liver, we are interested in the ability of specific fatty acids to cause liver cell death (“lipotoxicity”). We use cell culture and animal models to investigate how fat causes liver injury, and how the accumulation of toxic fatty acids in the liver might be avoided by dietary modifications such as lowering sugar consumption.

Selected Publications

• Hanson JC, Bostick MK, Campe CB, Kodali P, Lee G, Yan J, Maher JJ. Transgenic overexpression of interleukin-8 in mouse liver protects against galactosamine/endotoxin toxicity. J Hepatol 2006;44:359-367.
• Rizki G, Arnaboldi L, Gabrielli B, Lee G, Yan J, Ng R, Turner S, Badger TM, Pitas RE, Maher JJ. Mice fed a lipogenic diet lacking methionine and choline develop hypermetabolism and weight loss coincident with hepatic suppression of stearoyl-CoA desaturase-1. J Lipid Res 2006;47:2280-2290.
• Lee G, Yan J, Ng RK, Kakar S, Maher JJ. Polyunsaturated fat in the methionine-choline-deficient diet influences hepatic inflammation but not hepatocellular injury. J Lipid Res 2007;48:1885-1896.
• Maher JJ, Leon P, Ryan JC. Beyond Insulin Resistance: Innate Immunity in NASH. Hepatology 2008; 48:670-678.

My major interest is in viral hepatitis and the role of the host immune response. My work focuses on interactions among alcohol use, cannabis use and HIV co-infection on outcomes of HCV infection. We are currently evaluating the effect of light and moderate alcohol use, alone or in combination with cannabis, on the severity and rate of progression of liver disease in women co-infected with HCV and HIV. We are also studying adherence to antiretroviral therapy in HIV/HCV co-infected women and on HCV-specific and innate immune responses in persons co-infected with HCV and HIV. I work within the AIDS Clinical Trial Group to develop clinical trials in viral hepatitis and HIV and within the Women’s Interagency HIV Study (WIHS) to examine predictors of liver-related morbidity and mortality in a cohort of women with HIV/HCV infection.

Selected Publications

• Cohen MH, Grey D, Cook H, Anastos K, Seaberg E, Augenbraun M, Burian P, Peters M, Young M, French A. Awareness of Hepatitis C status and access to care among women with and at risk for HIV. J Gen Intern Med 2007;22:1689-1694.
• Strickler HD, Howard AA, Peters MG, et al. The Insulin-like Growth Factor Axis and Its Role in Liver Disease Among HCV/HIV Co-infected Women. AIDS 2008:527-531.
• Ishida JH, Peters MG, Jin C, Louie K, Tan V, Bacchetti P, Terrault NA. Influence of cannabis use on severity of hepatitis C disease. Clin Gastroenterol Hepatol 2008:6(1):69-75
• Buxbaum J, Qian P, Allen PM, Peters MG. Hepatitis resulting from liver-specific expression and recognition of self-antigen. J Autoimmunity 2008, in press.

My research uses the power of forward genetics in zebrafish to investigate the cellular and molecular mechanisms underlying liver development. Since liver development has not been characterized in zebrafish, an initial goal has been to establish the details of the process in wild-type organisms. Experiments make use of a transgenic line that expresses GFP in the developing gut and associated organs including the liver. This makes it possible to track the cellular movements leading to liver development, along with the expression pattern of relevant genes of interest. Our lab recently demonstrated that Wnt2b, Bmp and Fgf signaling are each important in the early stages of liver development in zebrafish. More recently, the lab has used single cell lineage tracing in zebrafish to investigate the origin of hepatic progenitors in vivo and to analyze cell fate decisions that lead to development of liver vs. pancreas.

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.

My research focuses on the natural history and treatment of hepatitis C virus (HCV) and hepatitis B virus (HBV), particularly in special populations, including those undergoing liver transplantation. Work in progress addresses the natural history of post-transplant disease and specific therapies to prevent infection or modify HCV and HBV disease progression and loss of grafts from recurrent disease. Our virological analyses are focused on characterization of viral mutations that occur in liver transplant recipients receiving antiviral therapies and assessment of the effect of these variant viruses on the natural history and severity of disease post-transplantation. Knowledge of these factors may allow improved organ allocation by identifying subsets of patients with HCV recurrence in liver grafts who would be favorable or unfavorable candidates for retransplantation.

Selected Publications

• Conjeevaram HS, Fried MW, Jeffers LJ, Terrault NA, et al. for the Virahep-C Study Group. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology. 2006;131:470-477.
• Terrault NA, Shiffman ML, Lok AS, Saab S, Tong L, Brown RS, Everson GT, Reddy KR, Fair JH, Kulik LM, Pruett TL, Seeff LB; A2ALL Study Group. Outcomes in hepatitis C virus-infected recipients of living donor vs. deceased donor liver transplantation. Liver Transpl. 2007;13:122-129.
• Galun E, Terrault NA, Eren R, Zauberman A, Nussbaum O, Terkieltaub D, Zohar M, et al. Clinical evaluation (Phase I) of a human monoclonal antibody against hepatitis C virus: safety and antiviral activity. J Hepatol 2007;46:37-44.
• Ishida JH, Peters MG, Jin C, Louie K, Tan V, Bacchetti P, Terrault NA. Influence of cannabis use on severity of hepatitis C disease. Clin Gastroenterol Hepatol 2008;6:69-77.

The overall goal of my laboratory is to discover strategies to prevent and treat fibrotic diseases of the liver and gut by elucidating the molecular and cellular signals that mediate pericyte/myofibroblast behavior. In one project we are elucidating the signals that control the biology of hepatic stellate cells, focusing specifically on the regulation and role of stellate cell contraction and migration. We are also developing a transgenic mouse model in which hepatic stellate cells can be selectively ablated, to further investigate the role played by these cells in acute liver injury, hepatic regeneration and cirrhosis. A third project in the lab focuses on subepithelial myofibroblast relaxation in intestinal injury. In this study we are clarifying the regulation of relaxation by natriuretic peptide and nitric oxide. We are also working to develop mouse models of intestinal stricture formation.

Selected Publications

• Melton, AC, Datta, A, Yee, Jr HF, [Ca2+]i-independent contractile force generation by rat hepatic stellate cells in response to endothelin-1, Am J Physiol, 290: G7-G13, 2006.
• Melton, AC, Yee, Jr HF, Hepatic stellate cell protrusions couple platelet-derived growth factor BB to chemotaxis, Hepatology, 45: 1446-53, 2007.
• Melton, AC, Soon, R, Park, JG, Martinez, L, DeHart, G, Yee, Jr HF, Focal adhesion disassembly is an essential early event in hepatic stellate cell chemotaxis, Am J Physiol, 293: G1272-80, 2007.

My research focuses on viral hepatitis, with the goals of understanding viral pathogenesis and identifying novel drug targets. Recently, we have developed a novel transgenic mouse model of hepatocarcinogenesis induced by hepatitis B virus (HBV) and are currently determining the molecular mechanisms involved. We are also characterizing a novel transcription factor that is up-regulated by the unfolded protein response and activates one of the major HBV promoters.

Selected Publications

• Huang ZM, Tan T, Yoshida H, Mori K, Ma Y, Yen TSB. Activation of Hepatitis B Virus S Promoter by a Cell-Type Restricted IRE1-Dependent Pathway Induced by Endoplasmic Reticulum Stress. Mol Cell Biol 2005;25:7522-7533.
• Zheng Y, Chen WL, Louie SG, Yen TSB, Ou JHJ. Hepatitis B virus promotes hepatocarcinogenesis in transgenic mice. Hepatology 2007;45:16-21.
• Sir D, Chen WL, Choi J, Wakita T, Yen TSB and Ou JH. Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response. Hepatology 2008, in press.

Our research group studies basic mechanisms involved in immunopathogenesis of acute and chronic hepatitis B virus (HBV) infection, as well as basic principles in both innate and adaptive immunity to viral pathogens. By identifying the role of both innate and adaptive immunity in HBV clearance and virus-induced liver damage, we hope to develop strategies for therapeutic intervention. Our approach is to model hepatitis B pathogenesis in mice, to explore candidate mechanisms, and to test their applicability to human disease. Such inter-species experimental transitions are crucial to definitively understanding human disease pathogenesis. New results from our mouse models have revealed disease mechanisms that we believe are likely involved in human HBV immunopathogenesis. The hypotheses formulated from these results have recently provided our laboratory the exciting opportunity to launch our first human studies in pursuit of our goals.

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.

My research focuses on the association between hepatitis C virus (HCV) and diabetes. My group previously evaluated mechanisms of insulin resistance and secretion in a large cohort of hepatitis C patients, and is now examining how HCV affects insulin action among the high risk Latino population. We are studying insulin action over time, with and without HCV treatment, using direct measures of insulin secretion and insulin action. Through a pilot project focused on community research, we are also evaluating liver cancer screening practices in hepatitis B-infected Asians as well as patient outcomes who undergo screening for liver cancer.

Selected Publications

• Khalili M, Watson J, Bass N, Ascher N, Roberts J, Terrault N. New Onset Diabetes Mellitus After Liver Transplantation: The Critical Role of Hepatitis C Infection. Liver Transplantation 2004;10:349-355.
• Khalili M, Fisher E, Bernstein D, Lentz E, Barylski C, Hoffman-Terry M. Peginterferon alfa-2a With or Without Ribavirin in HCV/HIV Coinfected Patients: Partially-Blinded and Randomized Multicenter Trial. Dig Dis Sci 2005;50:1148-55.
• 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;20:1-9.

My research interest is in hepatitis C virus (HCV) variants and immune responses in injection drug users. We are examining rates of re-infection or genotype switching over time, describing rates and predictors of liver disease progression and examining causes of death. We are also comparing hematological and virological changes during interferon-based therapy in subjects with HCV alone to those with HIV-HCV co-infection.

Selected Publications

• Monto A, Kakar S, Dove LM, Bostrom A, Miller EL, Wright TL. Contributions to hepatic fibrosis in HIV-HCV coinfected and HCV monoinfected patients. Am J of Gastroenterol 2006;101:1509-1515.
• Seal KH, Monto A , Dove L, Shen H, Vittinghoff E, Tracy D, Miller E, Lau E, Wright TL. The association of human immunodeficiency virus infection with spontaneous hepatitis C virus resolution and level of viremia among injection drug users. Dig Dis Sci 2007; 52: 3423-3430.
• 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.

The liver has the capacity to regenerate, but this ability is lost in chronic liver disease. Because donor organs for liver transplantation are sparse, our goal is to establish novel means to promote liver regeneration. For example, we are investigating ways to induce bone marrow or pluripotent stem cells to differentiate into hepatocytes that can be transplanted into patients with end-stage liver disease. To this end, we are studying the origin of liver stem or progenitor cells and are working to understand the signals that direct their expansion and differentiation. In addition to losing its regenerative capacity, the diseased liver undergoes scarring and often develops cancer. Another goal of our laboratory is to understand the mechanisms that lead to this unfortunate chain of events, in particular with regard to the role of immature liver cells in the process of liver cancer initiation and promotion.

Selected Publications

• Rizvi AZ, Swain JS, Bailey AS, Decker AD, Willenbring H, Grompe M, Fleming WH, Wong MH. Bone marrow-derived cells regenerate intestinal epithelium by fusion with multipotent progenitors. Proc Natl Acad Sci. 2006;103:6321-6325.
• Willenbring H, Bailey AS, Jiang S, Anderson DA, Schroeder DA, Wong MH, Grompe M, Fleming WH. Myeloid lineage progenitors give rise to vascular endothelial cells. Proc Natl Acad Sci. 2006;103:13156-13161.
• Willenbring H, Sharma AD, Vogel A, Lee AY, Rothfuss A, Wang Z, Finegold M, Grompe M. Loss of p21 permits carcinogenesis from chronically damaged liver and kidney epithelial cells despite unchecked apoptosis. Cancer Cell. 2008;14:59-67.