Presentation on theme: "Bernard Bouscarel, Ph.D., D.Sc. Associate Professor of Biochemistry and Molecular Biology and of Medicine Director, Digestive Diseases Center Director,"— Presentation transcript:
Bernard Bouscarel, Ph.D., D.Sc. Associate Professor of Biochemistry and Molecular Biology and of Medicine Director, Digestive Diseases Center Director, Molecular Medicine Program
Cell signaling and bile acid metabolism Chemotherapy and TopoI inhibitor 1994 UDCA as a chemotherapeutic agent 2000 Bile acid and chemoprevention 2006 UDCA and cholestatic liver diseases Elucidation of hepatic hormonal and AA response Bile acids and skin fibroblast signaling Bile acids and fibroblast proliferation Bile acids and hepatic cell proliferation Bile acids, hormone AA responses and cirrhosis/diabetes Relationship between fibroblasts and HSC Hepatic fibrosis prevention Bile acids & Taurine transport Bile acids and hepatic signaling
CMCM Total PKC P-PKC -actin CTLCDCA (1) (2.13) (4.45) PKC phosphorylation glucagon Bile Acid DAG PIP 2 IP 3 Ca 2+ ? P P P ? ? ? GR P ? ? P PS DAG Ca 2+ PKC Catalytic domain Pseudosubstrate PLC GSGS AC ATP cAMP Cholestasis: Bile acids/ hormonal response Background: Hypothesis: Methods: PKC translocation 10’ 6’ 0’ Co-localization of GR & PKC 0’ 20’ Green: GR, Red: PKC , Yellow; merge GR phosphorylation CTL CDCA (25 M) PL WB (1)(3.0) Bile acids are responsible for the decreased hepatic glucagon responsiveness in cholestasis through a mechanism involving PKC and GR phosphorylation. Genomics, proteomics, and pharmacologic approaches to identify the relevant amino acids phosphorylated by bile acids leading to activation of PKC and inhibition of GR cellular response. Le et al. Am J Physiol Ikegami et al. Endocrinology Krilov et al. (in preparation) GR: glucagon receptor AC: adenylyl cyclase PLC: phospholipase C Cholestatic and cirrhotic patients (50-80%) display: glucose intolerance decreased gluconeogenic response to glucagon hepatic resistance to glucagon attenuation of glucagon-induced cAMP production Bile acids attenuate glucagon-induced cAMP production through a mechanism involving PKC
Fibrosis: Bile acids/ fibroproliferation Background: Hypothesis: Methods: Co-Inv. and Collaborators: Drs. Rojkind, Ceryak and Kashanchi Drs. Lin, Latham and Piper Chronic liver disease and cirrhosis in particular, is the 12th leading cause of death in US. Fibrosis is a hallmark of cirrhosis Hepatic stellate cells (HSC) are key in the development of liver fibrosis. ILK Cox2 Growth arrest /death Proliferation survival Normal HSC Cox2 ILK Fibrotic HSC Growth arrest /death Proliferation survival Zhang et al. Hepatology Meng et al. Am J Physiol Meng & Bouscarel (submitted) HSC CTLChol ILK Cox-2 CDCACTL Normal Cirrhosis FXR= farnesoid X receptor PKC= protein kinase C P38= p38 MAPK ILK= integlin-liked kinase PI3K AKT PKC FXR ILK Cox2 P38 Proliferation Bile acids BA stimulate COX-2-mediated cell cycle arrest/death. In fibrosis, this signal is blunted through increased ILK expression/ activation fibroproliferation. Isolation of HSC and Human skin fibroblasts (HSF) from control and patients with acute/chronic cholestasis. Pharmacologic, genomic, and proteomic methods to identify key determinants of fibroproliferation. Liver
Cancer: Bile acids/ topoisomerase I inhibitors Background: Purpose/ Methods: Compare the effect of various agents, BA, H + -pump inhibitor, PLC, CPT-11 analogs, CPT-11…. on: Tumor cell metastasis Survival rate Cell proliferation, apoptosis, cell cycle factors Tumor gene expression Colorectal cancer (CRC) is a leading cause of cancer- related death. Bile acids play an important role in the etiology of CRC. Certain bile acids (UDCA) may have chemotherapeutic properties against CRC. CPT-11 (Irinotecan, Camptostar ) is one of the leading anti-cancer drugs for CRC therapy. Liver Spleen Kidney Heart Lung Spleen Fluorescence intensity Liver 2 weeks later I.P. injection CPT-11 UDCA drinking MC-26 cells transfected with GFP Spleen Liver BALB/c mice Spleen Liver BALB/c mice Ikegami et al. Cancer Res Ikegami et al. Mol Cancer Ther Ikegami et al. (submitted) Hypothesis: UDCA enhances the antitumor chemotherapeutic action of CPT-11.
Bernard Bouscarel, PI Jiamping Meng, Senior Scientist Teruo Miyazaki, Post Doc Maryam Alrashid, 5th year IBS student Lada Krilov, 4th year IBS student Amy Nguyen, 2nd year IBS student Helen Johnston, 1st year IBS student (Rotation) Nara Lee, Undergraduate student Ivy Akid, Undergraduate student