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.

项目总结 在美国，胆汁淤积性肝病是进行性肝病的高度流行原因，具有 严重的发病率和死亡率。不幸的是，目前的医学疗法往往不能预防疾病。 病情发展，不能治愈。在过去的十年中，未折叠蛋白反应(UPR)，一种适应性的 细胞对内质网(ER)应激的反应与许多肝脏的发病有关 疾病。然而，UPR在肝脏胆汁酸毒性和胆汁淤积性肝损伤中的作用仍然很少。 明白了。肌醇需要酶1α/X盒结合蛋白1(α/XBP1)途径是一种高度 UPR在进化上保守的信号通路，既对肝脏有保护作用，又在 调节脂类代谢。这一建议的中心假设是肝脏IRE1α/XBP1s信号 调节胆汁酸代谢，胆汁酸信号进一步调节IRE1α/XBP1s通路。我们 初步数据表明，肝脏IRE1XBP1途径被胆汁淤积激活，是一种 减少胆汁淤积性肝损伤，调节胆汁酸代谢的重要保护性反应。因此， 我们将确定肝脏IRE1α/XBP1通路在胆汁淤积性肝脏调节中的作用 损伤(特异性目标1A)和胆汁酸合成(特异性目标1B)。肝脏FXR/SHP信号转导是一种 调节胆汁中许多基因和生理过程的基本胆汁酸反应途径 酸代谢。在初步研究中，我们证明了IRE1α/XBP1S通路受 FXR/SHP信号通路。因此，我们将定义FXR/SHP信号转导的调控机制 肝脏IRE1α/Xbp1s通路(特异性靶点2)。最后，FGF19是一种回肠激素，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，我们将 研究成纤维细胞生长因子19信号对IRE1XBP1信号通路的调节作用(特异性目标3)。我们的长- 学期目标是进一步发展一系列研究，表征IRE1α/XBP1的机制 而其他UPR信号通路可以减少胆汁淤积和其他形式的肝脏疾病时的肝脏损伤。这 该提案利用最先进的小鼠遗传学、分子生物学、蛋白质组学和生理学技术 进一步确定IRE1FXR/XBP1、α/SHP和FGF15/19信号通路在胆汁中的保护作用 酸损伤和胆汁淤积。这些研究可能有助于确定胆汁酸的新调节机制。 新陈代谢和IRE1α/XBP1信号通路可用于靶向新的治疗方法 胆汁淤积性肝病和其他肝病。