Cholestasis and the Unfolded Protein Response

胆汁淤积和未折叠的蛋白质反应

基本信息

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
项目类别：
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

项目摘要

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.

项目概要胆汁淤积性肝病是美国进行性肝病的高度普遍原因，不幸的是，目前的医学疗法常常不能预防疾病。在过去的十年中，未折叠蛋白反应（UPR）是一种适应性的疾病。细胞对内质网 (ER) 应激的反应与许多肝脏疾病的发病机制有关然而，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。肌醇需求酶 1α/X-box 结合蛋白 1 (IRE1α/Xbp1) 途径是一种高度了解的途径。 UPR 的进化上保守的信号通路，既能保护肝脏，又能在该提案的中心假设是肝脏 IRE1α/XBP1s 信号传导。调节胆汁酸代谢，胆汁酸信号进一步调节 IRE1α/XBP1s 通路。初步数据表明，肝脏 IRE1α/Xbp1 通路是由胆汁淤积激活的，是一种减少胆汁淤积性肝损伤和调节胆汁酸代谢的重要保护反应。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（具体目标 1A）和胆汁酸合成（具体目标 1B）。必需胆汁酸反应途径，调节胆汁中涉及的许多基因和生理过程在初步研究中，我们证明 IRE1α/XBP1s 途径受调节。因此，我们将定义FXR/SHP信号通路的调控机制。肝脏 IRE1α/Xbp1s 通路（具体目标 2）最后，FGF19 是一种回肠激素。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。表征 FGF19 信号传导对 IRE1α/Xbp1 通路的调节（具体目标 3）。短期目标是进一步开发一系列研究，表征 IRE1α/XBP1 的机制和其他 UPR 信号通路可减少胆汁淤积和其他形式的肝脏疾病期间的肝损伤。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IRE1α/XBP1、FXR/SHP和FGF15/19信号通路在胆汁中的保护作用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治疗的新疗法胆汁淤积性肝病和其他肝脏疾病。