Molecular Mechanisms of Toxin-InducedBiliary Atresia

毒素诱发胆道闭锁的分子机制

• 批准号: 9912763
• 负责人: Xiao Zhao
• 金额: $ 16.55万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-17 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912763
• 关键词: Advisory Committees; Aftercare; Animal Model; Biliary; Biliary Atresia; Biological; Biological Assay; Biology; Cells; Child; Childhood; Client; Data; Development; Disease; Disease Outbreaks; Dose; Environment; Epidemic; Epidemiology; Etiology; Event; Exhibits; Exposure to; Extrahepatic; Faculty; Foundations; Funding; Genes; Genetic; Genetic Predisposition to Disease; Glutathione Disulfide; Goals; Heat-Shock Proteins 70; Heat-Shock Proteins 90; Heat-Shock Response; Hepatobiliary; Hepatocyte; Heritability; Heterogeneity; Homeostasis; Human; In Vitro; Ingestion; Injury; Larva; Link; Liver; Liver diseases; Livestock; Mediating; Mentors; Metabolism; Modeling; Molecular; Molecular Chaperones; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Neonatal; Newborn Infant; Nonsense Mutation; Oxidation-Reduction; Pathogenesis; Pathway interactions; Patients; Perinatal Exposure; Pharmacology; Plants; Play; Population; Positioning Attribute; Predisposition; Proteins; Proteomics; Publishing; Research; Resistance; Resources; Risk Factors; Role; Signal Pathway; Stress; Syndrome; System; Toxic effect; Toxin; United States National Institutes of Health; Variant; Zebrafish; base; biological adaptation to stress; cholangiocyte; epigenetic regulation; exome sequencing; experimental study; genetic manipulation; in vivo; induced pluripotent stem cell; insight; intrahepatic; liver transplantation; new therapeutic target; novel; novel therapeutic intervention

PROJECT SUMMARY Biliary atresia (BA) is a neonatal cholangiopathy that is the leading indication for liver transplantation in the pediatric population. The etiology of human BA remains obscure, however, BA epidemics in newborn Australian livestock associated with maternal ingestion of the Dysphania species plant support a toxic etiology. Using an in vivo zebrafish biliary secretion assay, we have isolated biliatresone, a novel plant isoflavonoid with selective extrahepatic biliary toxicity that is likely responsible for the Dysphania BA syndrome (1). This toxin- mediated BA model recapitulates the cardinal features of human BA and thus can be used to model this rare but important pediatric liver disease. Biliatresone is a strong electrophile and we have shown that redox stress and proteomic stress play critical roles in biliatresone toxicity. Specifically, we have found that: 1) extrahepatic cholangiocytes exhibit a significantly more oxidized glutathione (GSH) redox potential both at baseline and after treatment with biliatresone compared to intrahepatic cholangiocytes and hepatocytes; and 2) biliatresone toxicity can be altered through pharmacologic and genetic manipulation of GSH redox homeostasis (2). The overarching goals of this proposal are to continue use biliatresone as an injury model for defining cholangiocyte stress responses to toxic insults and to explore the links between stress responses and genetic susceptibility to biliary injury. The proposal consists of two specific aims. In Aim 1, we will define mechanisms of liver redox heterogeneity that confer differential susceptibility to toxic injury in the zebrafish model. In Aim 2, we will define links between cholangiocyte proteomic and redox stress responses and genetic susceptibility to redox- induced cholangiocyte injury using zebrafish and human cholangiocytes derived from induced pluripotent stem cells. The proposed experiments will reveal novel information about the molecular mechanisms underlying the pathogenesis of BA that we hope will spur the development of new therapeutic strategies for BA and other cholangiopathies.

项目概要 胆道闭锁（BA）是一种新生儿胆管病，是肝移植的主要适应症。 儿科人群。人类 BA 的病因仍不清楚，然而，BA 在新生儿中流行 与母体摄入 Dysphania 植物相关的澳大利亚牲畜支持了有毒病因。 通过体内斑马鱼胆汁分泌测定，我们分离出了胆汁松，一种新型植物异黄酮，具有 选择性肝外胆道毒性可能是导致 BA 综合征的原因 (1)。这种毒素—— 介导的 BA 模型概括了人类 BA 的主要特征，因此可用于建模 这种罕见但重要的小儿肝脏疾病。 Biliatresone 是一种强亲电子试剂，我们已经证明氧化还原应激和蛋白质组应激起着至关重要的作用 胆阿曲松毒性中的作用。具体来说，我们发现：1）肝外胆管细胞表现出 在基线和治疗后，氧化型谷胱甘肽 (GSH) 氧化还原电位显着增加 胆阿曲松与肝内胆管细胞和肝细胞的比较； 2) 胆阿曲松的毒性可能是 通过 GSH 氧化还原稳态的药理学和基因操作来改变 (2)。首要的 该提案的目标是继续使用胆阿曲松作为定义胆管细胞应激的损伤模型 对毒性损伤的反应，并探讨应激反应与胆汁遗传易感性之间的联系 受伤。该提案包含两个具体目标。在目标 1 中，我们将定义肝脏氧化还原机制 异质性赋予斑马鱼模型对毒性损伤的不同易感性。在目标 2 中，我们将 定义胆管细胞蛋白质组和氧化还原应激反应与氧化还原遗传易感性之间的联系 使用源自诱导多能干的斑马鱼和人胆管细胞诱导胆管细胞损伤 细胞。 所提出的实验将揭示有关潜在分子机制的新信息 我们希望对 BA 发病机制的研究能够促进 BA 和其他疾病新治疗策略的开发 胆管病。