Molecular Mechanisms of Intrahepatic Cholestasis

肝内胆汁淤积的分子机制

基本信息

批准号：
8232088
负责人：
BENJAMIN L SHNEIDER
金额：
$ 31.12万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-20 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8232088
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

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

展开

项目摘要

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，不舒适和组织学进行性胆汁淤积（Byler病）。系统性表现涉及胰腺，肺，胃肠道和听觉系统。 FIC1疾病是由FIC1（ATP8B1）基因突变引起的，其功能仍然难以捉摸。我们在阐明FIC1疾病的病理生理学方面取得了重要进步。 Farnesoid X受体（FXR）介导的信号传导在患有FIC1疾病的儿童的回肠异常。我们已经在细胞培养中对FIC1疾病进行了建模。由于FIC1缺乏引起的FXR活性降低的转录效应包括肠道胆汁酸转运的增强。我们是第一个表明FIC1相关疾病的温和形式（即金砖四国）是由于FIC1功能及其膜靶向的部分缺陷而导致的，而严重疾病与完全没有功能有关。我们已经机械地连接了FIC1和FXR。 FIC1激活涉及磷脂酶D2（PLD2）和蛋白激酶C（PKC）的途径？信号传导途径导致磷酸化，核定位和FXR的激活。该R01提案旨在更全面地探索FIC1功能和疾病的分子机制。这些研究将从这些研究中产生新的见解，这将进一步了解胆汁淤积性肝病，正常的肝和肠道生理学，FIC1疾病的蛋白质非肝脏表现以及FIC1运输的生物学和临床后果。这些见解很可能会转化为广泛学科的治疗进步。这项研究将涉及三个特定目标，这些目标测试了通过PLD2和PKC信号的质膜FIC1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了许多改变。它还将检验以下假设：在人类中，FIC1疾病是FXR介导的信号通路的临界变化的结果。这些假设将通过以下特定目标进行检验； 1）表征受FIC1影响的信号转导途径，2）对FIC1疾病的分子机制的分析，3）检查人胆汁淤积的胆囊中FXR信号传导的检查。 FIC1疾病（又名Byler病或PFIC1）是一种复杂的多系统疾病，其机制尚不清楚。最近的分子发现提供了一个理解这种疾病（提供新疗法）并探索肝脏，胰腺，胃肠道和肺的基本生理学的机会。