Molecular Mechanisms of Intrahepatic Cholestasis

肝内胆汁淤积的分子机制

• 批准号: 8432036
• 负责人: BENJAMIN L SHNEIDER
• 金额: $ 29.23万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-20 至 2014-12-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8432036
• 关键词: Alagille Syndrome; Auditory system; Benign recurrent intrahepatic cholestasis; Bile Acids; Biliary; Biological; Cell Culture Techniques; Cell membrane; Cell model; Chemicals; Child; Cholestasis; Clinical; Complex; Conflict (Psychology); Defect; Discipline; Disease; Exogenous Factors; Functional disorder; Funding; Future; Gallbladder; Gastrointestinal tract structure; Genes; Genetic; Goals; Hepatic; Hepatocyte; Histologic; Human; Inflammatory; Intestines; Intrahepatic Cholestasis; Link; Liver; Liver diseases; Lung; Mediating; Membrane; Modeling; Molecular; Molecular Analysis; Molecular Chaperones; Mutation; Nuclear; Pancreas; Pathway interactions; Patients; Phosphoproteins; Phosphorylation; Physiology; Progressive intrahepatic cholestasis; Protein Kinase C; Proteins; Proteomics; Receptor Signaling; Regulation; Research; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Temperature; Testing; Therapeutic; Tissues; Translating; United States National Institutes of Health; cytokine; disease-causing mutation; enzyme activity; gain of function; ileum; insight; novel; novel therapeutic intervention; phospholipase D2; protein expression; protein transport; receptor; receptor-mediated signaling; response; trafficking

DESCRIPTION (from the applicant): FIC1 disease includes a spectrum of liver problems ranging from "benign" recurrent intrahepatic cholestasis (BRIC) to severe, unremitting and histologically progressive cholestasis (Byler Disease). Systemic manifestations involve the pancreas, lung, gastrointestinal tract and auditory system. FIC1 disease result from mutations in the FIC1 (ATP8B1) gene, whose function remains elusive. We have made important advances in unraveling the pathophysiology of FIC1 disease. Farnesoid X-Receptor (FXR) mediated signaling is abnormal in ileum of children with FIC1 disease. We have modeled FIC1 disease in cell culture. The transcriptional effects of reduced FXR activity due to FIC1 deficiency include enhanced intestinal and diminished canalicular bile acid transport. We are the first to show that milder forms of FIC1 related disease (i.e. BRIC) result from a partial defect in both FIC1 function and its membrane targeting, while severe disease is associated with a complete absence of function. We have mechanistically linked FIC1 and FXR. FIC1 activates a pathway involving Phospholipase D2 (PLD2) and Protein Kinase C (PKC) ? signaling pathway leading to phosphorylation, nuclear localization and activation of FXR. This R01 proposal seeks to more fully explore the molecular mechanisms of FIC1 function and disease. Novel insights will be generated from these studies that will further our understanding of cholestatic liver disease, normal hepatic and intestinal physiology, the protean nonhepatic manifestations of FIC1 disease, and the biological and clinical consequences of FIC1 trafficking. It is very likely that these insights will translate into therapeutic advances in a broad range of disciplines. This research will involve three specific aims that test the hypothesis that plasma membrane FIC1 signals through PLD2 and PKC? leading to numerous alterations in the expression and phosphorylation of key signaling molecules including FXR. It will also test the hypothesis that in humans FIC1 disease is the result of critical changes in FXR-mediated signaling pathways. These hypotheses will be tested with the following specific aims; 1) Characterization of the signal transduction pathways influenced by FIC1, 2) Analysis of the molecular mechanisms of FIC1 disease, 3) Examination of FXR signaling in gallbladder in human cholestasis. FIC1 disease (aka Byler Disease or PFIC1) is a complex multisystem disorder whose mechanism(s) are not known. Recent molecular discoveries provide an opportunity to understand this disease (providing new therapies) and to explore basic physiology of the liver, pancreas, gastrointestinal tract and lungs.

描述（来自申请人）：FIC1疾病包括一系列肝脏问题，从“良性”复发性肝内胆汁淤积（BRIC）到严重、持续性和组织学进展性胆汁淤积（拜勒病）。全身表现涉及胰腺、肺、胃肠道和听觉系统。 FIC1 疾病是由 FIC1 (ATP8B1) 基因突变引起的，该基因的功能仍然难以捉摸。我们在阐明 FIC1 疾病的病理生理学方面取得了重要进展。 FIC1 疾病儿童的回肠中法尼醇 X 受体 (FXR) 介导的信号传导异常。我们在细胞培养中模拟了 FIC1 疾病。 FIC1 缺陷导致 FXR 活性降低的转录效应包括肠道胆汁酸转运增强和小管胆汁酸转运减少。我们首次证明，较轻形式的 FIC1 相关疾病（即 BRIC）是由 FIC1 功能及其膜靶向部分缺陷引起的，而严重疾病则与功能完全缺失有关。我们已将 FIC1 和 FXR 机械连接起来。 FIC1 激活涉及磷脂酶 D2 (PLD2) 和蛋白激酶 C (PKC) 的途径？导致 FXR 磷酸化、核定位和激活的信号通路。该 R01 提案旨在更全面地探索 FIC1 功能和疾病的分子机制。这些研究将产生新的见解，进一步加深我们对胆汁淤积性肝病、正常肝脏和肠道生理学、FIC1 疾病多变的非肝脏表现以及 FIC1 贩运的生物学和临床后果的理解。这些见解很可能会转化为广泛学科的治疗进展。这项研究将涉及三个具体目标，以检验质膜 FIC1 通过 PLD2 和 PKC 发出信号的假设？导致包括 FXR 在内的关键信号分子的表达和磷酸化发生大量改变。它还将检验以下假设：人类 FIC1 疾病是 FXR 介导的信号通路发生重大变化的结果。这些假设将通过以下具体目标进行检验； 1）受FIC1影响的信号转导途径的表征，2）FIC1疾病的分子机制分析，3）人类胆汁淤积胆囊中FXR信号的检查。 FIC1 疾病（又名拜勒病或 PFIC1）是一种复杂的多系统疾病，其机制尚不清楚。最近的分子发现为了解这种疾病（提供新疗法）和探索肝脏、胰腺、胃肠道和肺的基本生理学提供了机会。