Regional Cholangiocyte Stress Responses in Biliary Disease

胆道疾病中的局部胆管细胞应激反应

• 批准号: 9381356
• 负责人: MICHAEL A PACK
• 金额: $ 40.25万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-18 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381356
• 关键词: Adult; Affect; Anatomy; Anger; Antioxidants; Bile Duct Diseases; Bile Duct Epithelium; Bile duct carcinoma; Bile fluid; Biliary; Biliary Atresia; Caustics; Cell Culture Techniques; Cells; Child; Childhood; Cholangiocarcinoma; Chromatin; Congenital atresia of extrahepatic bile duct; Consumption; Data; Detergents; Development; Disease; Disease Outbreaks; Dose; Duct (organ) structure; Ductal Epithelial Cell; Engineering; Enzymes; Epidemic; Epigenetic Process; Epithelial Cells; Extrahepatic; Gene Expression; Gene Mutation; Generations; Genes; Genetic Predisposition to Disease; Genetic Transcription; Glutathione; Glutathione Metabolism Pathway; Goals; Heat shock proteins; Heat-Shock Response; Hepatocyte; Heterogeneity; Human; Human Pathology; Impairment; Injury; Intrahepatic Cholangiocarcinoma; Isocitrate Dehydrogenase; Isoflavones; KRAS2 gene; Laboratories; Larva; Link; Liquid substance; Liver; Liver Failure; Livestock; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolic; Metabolism; Metaphor; Mitochondria; Modeling; Molecular Chaperones; Mutate; Mutation; NADP; Natural regeneration; Oncogenic; Organelles; Oxidation-Reduction; Oxidative Stress; Oxides; Pathogenesis; Pattern; Phosphoproteins; Physiological; Plants; Play; Population; Predisposition; Primitive foregut structure; Production; Property; Proteomics; Reactive Oxygen Species; Reduced Glutathione; Regulator Genes; Rest; Risk; Risk Factors; Role; Signal Transduction; Somatic Mutation; Stress; System; Toxic effect; Toxin; Translating; Variant; Vertebrates; Work; Zebrafish; bile duct; bile salts; biliary tract; biological adaptation to stress; cholangiocyte; combat; in vivo; induced pluripotent stem cell; intrahepatic; liver transplantation; mutant; novel; oxidative damage; prevent; progenitor; response; stressor; transcription factor

PROJECT SUMMARY Diseases of the biliary system are uncommon, however, collectively they comprise a significant percentage of the indications for liver transplantation in adult and pediatric populations. The pathogenesis of these disorders likely involves cellular responses to the harmful effects of bile, to which epithelial cells lining the bile ducts are continuously exposed. Bile toxicity arises largely from the oxidative damage caused by bile salts, whose detergent properties disrupt intracellular organelles, particularly mitochondria. Bile duct epithelial cells, also known as cholangiocytes, have evolved strategies for preventing bile toxicity in addition to having robust anti-oxidant defense systems, which are present in all cells to combat reactive oxygen species generated during normal metabolism. Recent work from my laboratory using the zebrafish system has identified regional susceptibilities to redox stress imparted by the biliary toxin biliatresone, which is an isoflavone recovered from Dysphania species plants responsible for outbreaks of epidemic biliary atresia (BA) in livestock. We have identified differences in the glutathione redox state in extra-hepatic and intra-hepatic cholangiocytes (EHC; IHC), and their ability to mitigate oxidative stress. This suggests that variation in cholangiocyte redox defenses may play a role in the pathogenesis of other biliary diseases. The goal of this proposal is to study the mechanisms responsible for this variation by exploiting the strengths of the zebrafish system. In aim 1, we will examine basal and stress-induced changes in glutathione metabolism in IHC and EHC. In aim 2, we will examine transcriptional mediators of basal and inducible stress responses in IHC and EHC, and determine whether they evolve from developmentally encoded differences in epigenetic regulators of gene transcription. In aim 3, we will examine the role of proteomic stress responses in redox induced biliary injury, focusing on a co- chaperone we have linked to human BA. In aim 4, we will study the differential effects in IHC and EHC of IDH gene mutations found in human bile duct cancers that have been shown to alter NADPH and glutathione metabolism in other cancers. The long term goal of these studies is to translate discoveries made in the zebrafish to humans using mammalian in vivo and cell culture models.

项目摘要 胆道系统疾病并不常见，然而，它们共同构成了一个重要的疾病。 成人和儿童人群中肝移植适应症的百分比。的 这些疾病的发病机制可能涉及对胆汁有害作用的细胞反应， 衬在胆管上的上皮细胞持续暴露。胆汁毒性主要来自于 胆汁盐引起的氧化损伤，其去污剂特性破坏细胞内细胞器， 尤其是线粒体。胆管上皮细胞，也称为胆管细胞， 除了具有强大的抗氧化防御系统外， 存在于所有细胞中，以对抗正常代谢过程中产生的活性氧。 我的实验室最近使用斑马鱼系统的工作已经确定了区域性的易感性， 氧化还原应激由胆毒素胆甾三酮引起，胆甾三酮是从Dysphania中回收的一种毒素 种植物负责暴发流行性胆道闭锁（BA）的牲畜。我们已经确定 肝外和肝内胆管细胞（EHC; IHC）中谷胱甘肽氧化还原状态的差异， 以及它们减轻氧化应激的能力。这表明胆管细胞氧化还原的变化 防御可能在其他胆道疾病的发病机制中起作用。 本提案的目标是通过利用 斑马鱼系统的优势。在目标1中，我们将检查基础和应激诱导的变化， IHC和EHC中的谷胱甘肽代谢。在aim 2中，我们将检查基础转录介质， 和诱导应激反应，并确定它们是否从 基因转录的表观遗传调节因子的发育编码差异。在目标3中，我们 研究蛋白质组应激反应在氧化还原诱导的胆道损伤中的作用，重点是共同的， 与人类BA相关的伴侣蛋白在目的4中，我们将研究IHC和EHC中的差异效应 在人类胆管癌中发现的IDH基因突变已被证明可以改变NADPH， 其他癌症中的谷胱甘肽代谢。这些研究的长期目标是将发现转化为 使用哺乳动物体内和细胞培养模型在斑马鱼中向人类制造。