Cholestasis and the Unfolded Protein Response

胆汁淤积和未折叠的蛋白质反应

• 批准号: 9750742
• 负责人: Richard M Green
• 金额: $ 35.55万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750742
• 关键词: Affect; Agonist; American; Applications Grants; Bile Acid Biosynthesis Pathway; Bile Acids; Binding Proteins; Cell Culture Techniques; Cholestasis; Cirrhosis; Clinical; Clinical Treatment; Clinical Trials; Data; Development; Disease; Disease Progression; Enzymes; FGF19 gene; Future; Gene Proteins; Genes; Genetic; Goals; Hepatic; Hormones; Injury; Inositol; Investigation; Lead; Liver; Liver Failure; Liver diseases; Malignant neoplasm of liver; Medical; Metabolic; Metabolism; Modeling; Molecular Biology; Morbidity - disease rate; Mus; Names; Nuclear Receptors; Pathogenesis; Pathway interactions; Pharmacology; Physiological; Physiological Processes; Process; Proteins; Proteomics; Regulation; Research; Role; Signal Pathway; Signal Transduction; Techniques; Testing; Toxic effect; United States; XBP1 gene; bile salts; cholestatic liver disease; endoplasmic reticulum stress; gene function; innovation; lipid metabolism; liver injury; mortality; new therapeutic target; novel; protective effect; response; therapeutic target

PROJECT SUMMARY Cholestatic liver diseases are highly prevalent causes of progressive liver disease in the United States with a significant morbidity and mortality. Unfortunately, current medical therapies frequently do not prevent disease progression and are not curative. Over the past decade, the Unfolded Protein Response (UPR), an adaptive cellular response to Endoplasmic Reticulum (ER) stress, has been implicated in the pathogenesis of many liver diseases. However, the role of the UPR in hepatic bile acid toxicity and cholestatic liver injury remains poorly understood. The Inositol-Requiring Enzyme 1α/X-box binding protein 1 (IRE1α/Xbp1) pathway is a highly evolutionarily conserved signaling pathway of the UPR that is both protective to the liver and is important in the regulation of lipid metabolism. The central hypothesis of this proposal is that hepatic IRE1α/XBP1s signaling regulates bile acid metabolism, and that bile acid signaling further regulates the IRE1α/XBP1s pathway. We show preliminary data demonstrating that the hepatic IRE1α/Xbp1 pathway is activated by cholestasis, is an important protective response to reduce cholestatic liver injury and regulates bile acid metabolism. Therefore, we will determine the role of the hepatic IRE1α/XBP1 pathway in the regulation of cholestatic liver injury (Specific Aim 1A) and bile acid synthesis (Specific Aim 1B). Hepatic FXR/SHP signaling is an essential bile acid-responsive pathway that regulates many genes and physiologic processes involved in bile acid metabolism. In preliminary studies, we demonstrated that the IRE1α/XBP1s pathway is regulated by the FXR/SHP signaling pathway. Thus, we will define the regulatory mechanisms of FXR/SHP signaling on the hepatic IRE1α/Xbp1s pathway (Specific Aim 2). Finally, FGF19 is an ileal hormone produced in response to bile acids that regulates bile acid synthesis and other hepatic processes. Therefore, we will characterize the regulation of the IRE1α/Xbp1 pathway by FGF19 signaling (Specific Aim 3). Our long- term goal is to further develop a line of research characterizing the mechanisms by which the IRE1α/XBP1s and other UPR signaling pathways reduce liver injury during cholestasis and other forms of liver disease. This proposal utilizes state-of-the-art mouse genetics, molecular biology, proteomics and physiologic techniques to further determine the protective role of the IRE1α/XBP1, FXR/SHP and FGF15/19 signaling pathways in bile acid injury and cholestasis. These investigations may help identify novel regulatory mechanisms of bile acid metabolism and IRE1α/XBP1 signaling that can be used to target new therapies for the treatment of cholestatic liver disease and other hepatic disorders.

项目摘要 在美国，胆汁淤积性肝疾病是美国进行性肝脏疾病的高度普遍原因 显着的发病率和死亡率。不幸的是，当前的医疗疗法经常不会预防疾病 进展，无法治愈。在过去的十年中，展开的蛋白质反应（UPR），一种自适应 在许多肝脏的发病机理中隐含了细胞对内塑性网状（ER）应激的反应 疾病。但是，UPR在肝胆汁酸毒性和胆汁淤积性肝损伤中的作用仍然很差 理解齿。肌醇的酶1α/X-box结合蛋白1（IRE1α/XBP1）途径是高度 IPR的进化配置的信号通路均受到肝脏的保护，在 调节脂质代谢。该提议的中心假设是肝IRE1α/XBP1S信号传导 调节胆汁酸的代谢，该胆汁酸信号传导进一步调节IRE1α/XBP1S途径。我们 显示初步数据，表明肝IRE1α/XBP1途径被胆汁淤积激活，是一种 重要的保护性反应以减少胆固性肝损伤并调节胆汁酸代谢。所以， 我们将确定肝脏IRE1α/XBP1途径在胆固醇肝脏调节中的作用 损伤（特定目标1A）和胆汁酸合成（特定目标1B）。肝FXR/SHP信号是 必需的胆汁酸反应性途径，该途径调节了许多胆汁中涉及的基因和生理过程 酸代谢。在初步研究中，我们证明了IRE1α/XBP1S途径由 FXR/SHP信号通路。这，我们将在上定义FXR/SHP信号的调节机制 肝IRE1α/XBP1S途径（特定目标2）。最后，FGF19是在 对调节胆汁酸合成和其他肝脏过程的胆汁酸的反应。因此，我们会的 通过FGF19信号传导来表征IRE1α/XBP1途径的调节（特定AIM 3）。我们的长期 术语目标是进一步开发一系列研究，以表征IRE1α/XBP1S的机制 其他UPR信号通路可减少胆汁淤积和其他形式的肝病期间的肝损伤。这 提案利用最先进的小鼠遗传学，分子生物学，蛋白质组学和生理技术 进一步确定胆汁中IRE1α/XBP1，FXR/SHP和FGF15/19信号通路的受保护作用 酸性损伤和胆汁淤积。这些研究可能有助于确定胆汁酸的新调节机制 代谢和IRE1α/XBP1信号传导可用于靶向新疗法以治疗 胆固性肝病和其他肝病。