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Bile Acid and Sphingosine-1-phosphate Receptor-mediated Signaling in Cholestasis

胆汁酸和 1-磷酸鞘氨醇受体介导的胆汁淤积信号传导

基本信息

批准号：
9024718
负责人：
PHILLIP B HYLEMON
金额：
$ 41.17万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9024718
关键词：
Apical Bile Acids Bile fluid Biology Cell Proliferation Cell membrane Cells Chemicals Cholestasis Chronic Data Diffusion Disease Disease Progression Down-Regulation Etiology Functional disorder G-Protein-Coupled Receptors Gene Expression Genes Growth Hepatocyte Histone Acetylation Histones Homeostasis Human Impairment Inflammation Inflammatory Ligation Link Liver Liver Fibrosis Liver diseases MAP3K1 gene MAPK3 gene Mediating Mitogen-Activated Protein Kinases Modeling Molecular Morbidity - disease rate Mus Nuclear Pathway interactions Patients Phosphotransferases Physiological Play Primary biliary cirrhosis Protein Kinase C Proteins Proto-Oncogene Proteins c-akt Reporting Role Serum Signal Pathway Signal Transduction Sodium Sphingosine Sphingosine-1-Phosphate Receptor Staging System Taurine Cholate Testing Therapeutic Up-Regulation apical membrane base basolateral membrane bile acid transporter bile duct bile formation bile salts cell motility cholangiocyte clinical application clinically significant cytokine effective therapy genetic inhibitor inhibitor/antagonist liver injury liver transplantation migration mortality mouse model novel novel strategies primary sclerosing cholangitis public health relevance receptor receptor coupling receptor-mediated signaling small hairpin RNA small molecule sphingosine kinase theories tool

项目摘要

DESCRIPTION (provided by applicant): Cholangiocytes, which form the bile duct system in the liver, are the major target cells in a number of human cholestatic liver diseases. Although there has been significant improvement in the understanding of the pathophysiology of disease progression over the past two decades, the underlying cellular/molecular mechanisms remain largely unknown. Cholangiocytes are continuously exposed to high concentrations of bile salts at their apical membranes. Bile acids taken up by an apical sodium bile acid transporter (ASBT) on cholangiocytes are unidirectionally transported across the cell and secreted via specific transporters (MDR3 and Ostα/Ostβ) on the basolateral membrane. ASBT has been reported to be regulated by changes in bile acid concentration and inflammatory cytokines. Bile acids taken up by cholangiocytes have been reported to activate a number of intracellular signaling pathways including: PKC, PI3K, MAP Kinase, and ERK 1/2 allowing for normal physiological homeostasis. Loss of ASBT allows only conjugated bile acids (CBAs) to activate plasma membrane receptors as hydrophilic bile acids cannot easily enter cells by simple diffusion. We have recently reported that CBAs activate the AKT and ERK1/2 signaling pathways via the G protein coupled receptor (GPCR) sphingosine-1-phosphate receptor 2 (S1PR2) in hepatocytes and cholangiocytes. The levels of CBAs in serum and liver are significantly elevated in chronic cholestasis, which is correlated with bile duct obstruction. Our preliminary data indicates that: 1 S1PR2 is the predominant S1P receptor expressed in cholangiocytes; 2) taurocholate (TCA)-induced cell proliferation and migration are inhibited by a specific shRNA and an antagonist of S1PR2 in cholangiocytes; 3) bile duct ligation (BDL) induces the up-regulation of S1PR2 gene expression and down-regulation of ASBT expression in mouse primary cholangiocytes; 4) BDL- induced cholangiocyte proliferation and liver fibrosis are significantly reduced in S1PR2-/- mice; 5) both S1PR2 and SphK2 are up-regulated in the liver of mdr2-/- mice (a PSC mouse model). In addition, it has been reported that TCA concentration was dramatically elevated in the liver and serum after BDL in mice. Based on these studies and our preliminary results, we HYPOTHESIZE that CBA-mediated activation of the S1PR2/SphK2 signaling cascades plays a critical role in promoting chronic cholangiopathy in cholestatic liver diseases. Three specific aims are proposed to test our central hypothesis. 1) To define the role of S1PR2 and SphK2 in CBA-mediated cholestatic liver injury using the BDL mouse model; 2) To identify the molecular/cellular mechanisms by which CBA-mediated S1PR2/SphK2 activation promotes cholestatic liver injury; 3) To test the therapeutic strategy for cholestatic liver injury by targeing S1PR2/SphK2 using chemical inhibitors and genetic tools in mdr2-/- mice, a cholestasis model of PSC. Completion of these specific aims will not only identify the potential cellular/molecular mechanisms involved in the initiation and progression of cholestatic liver diseases, but will also establish a novel theory in bile acid and S1P biology.