Cholestasis and the Unfolded Protein Response

胆汁淤积和未折叠的蛋白质反应

• 批准号: 8446092
• 负责人: Richard M Green
• 金额: $ 33.6万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446092
• 关键词: Affect; American; Applications Grants; Attenuated; Binding Proteins; Biochemical; Boxing; Cellular biology; Cholestasis; Cholic Acids; Cirrhosis; Data; Development; Disease; Disease Progression; Feedback; Genetic; Goals; Hepatic; Hepatotoxicity; In Vitro; Injury; Investigation; Lead; Life; Lipid Biochemistry; Lipids; Liver; Liver Failure; Liver diseases; Mediating; Medical; Metabolism; Molecular Biology; Mus; Names; Natural History; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Predisposition; Primary biliary cirrhosis; Proteins; RNA Splicing; Research; Role; Signal Pathway; Techniques; Therapeutic; Toxic effect; United States; Ursodeoxycholic Acid; attenuation; bile salts; dietary supplements; drug development; endoplasmic reticulum stress; feeding; gene synthesis; in vivo; liver transplantation; novel; prevent; primary sclerosing cholangitis; protective effect; response; therapeutic target

DESCRIPTION (provided by applicant): Cholestatic liver diseases are highly prevalent causes of progressive liver disease in the United States and are a common indication for liver transplantation. Unfortunately, current medical therapies are not curative and may not prevent disease progression. 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. The role of the UPR in hepatic bile salt toxicity and cholestatic liver disease, however, remains unexplored. X-box binding protein 1-spliced (XBP1s) is a key regulatory molecule of the UPR that our preliminary data indicates is protective from bile salt injury. The central hypothesis of this proposal is that XBP1s is protective to the live during cholestasis~ and attenuated hepatic expression of XBP1s results in diminished expression of liver bile salt transporters and increased susceptibility to hepatic bile salt liver injury. Thus, in this proposal we will feed diets supplemented with cholic acid to mice and define the role of XBP1s and downstream targets in hepatic bile salt injury (Specific Aim #1). CYP7a1 is the rate-limiting step in bile salt synthesis, and inhibition of CYP7a1 expression and activity can act as a negative feedback mechanism to reduce the bile salt pool. We present preliminary data indicating that activation of the hepatic UPR markedly reduces expression of hepatic CYP7a1, likely via a XBP1s- mediated pathway. Thus, we will determine that the Unfolded Protein Response and XBP1s suppress hepatic Cyp7a1 expression, function and bile salt synthesis (Specific Aim #2). Finally, in order to directly determine that attenuation of hepatic XBP1s expression increases susceptibility to bile salt hepatotoxicity, we will develop genetically-modified mice with a liver-specific deletion of XBP1. We will develop liver-specific XBP1(-/-) mice in order to confirm the protective role, and define the protective mechanisms, of XBP1s in liver bile salt injury (Specific Aim #3). While this proposal focuses on hepatic XBP1s, the long-term goal is to develop a line of research to identify UPR signaling pathways that can serve as therapeutic targets for the treatment of cholestatic liver diseases. This proposal utilizes state-of-the-art mouse genetics, molecular biology and lipid biochemical techniques to further our understanding of the protective role of XBP1s in bile salt injury and cholestasis. Investigations identifying the role of the XBP1s signaling pathway and its effects on bile salt-induced liver injury may identify a novel pathway and potential targets for drug development to treat cholestatic liver diseases. PUBLIC HEALTH RELEVANCE: Cholestatic liver diseases are common causes of progressive liver disease that can lead to cirrhosis and hepatic failure. Unfortunately, there are few medical therapies for cholestatic liver diseases. We will study role of bile salts in liver injury, and the mechanisms and protective effects of a liver protein named XBP1s in preventing hepatic bile salt injury.

描述（由申请人提供）：胆固性肝病是美国进行性肝脏疾病的高度普遍原因，是肝移植的常见指示。不幸的是，当前的医疗疗法无法治愈，可能不会阻止疾病进展。在过去的十年中，展开的蛋白质反应（UPR）是对内质网应激的自适应细胞反应，与许多肝病的发病机理有关。然而，UPR在肝胆汁盐毒性和胆汁淤积性肝病中的作用仍未得到探索。 X-box结合蛋白1分解（XBP1）是我们的初步数据表明的UPR的关键调节分子，可保护胆汁盐损伤。该提议的中心假设是XBP1在胆汁淤积过程中对生物具有保护作用，并减弱XBP1S的肝表达导致肝胆汁盐转运蛋白表达降低，并增加对肝胆汁盐肝损伤的敏感性。 因此，在此提案中，我们将喂食补充胆酸的饮食为小鼠，并定义XBP1和下游靶标在肝胆汁盐损伤中的作用（特定的目标＃1）。 CYP7A1是胆汁盐合成的限速步骤，CYP7A1表达和活性的抑制可以作为减少胆汁盐池的负反馈机制。我们提供了初步数据，表明肝UPR的激活显着降低了表达 肝CYP7A1，可能是通过XBP1S介导的途径。因此，我们将确定展开的蛋白质反应和XBP1抑制肝CYP7A1表达，功能和胆汁盐合成（特定目标＃2）。 最后，为了直接确定肝XBP1表达的衰减会增加对胆汁盐肝毒性的敏感性，我们将开发具有XBP1肝特异性缺失的遗传改性小鼠。我们将开发肝特异性XBP1（ - / - ）小鼠，以确认保护性作用，并定义肝胆汁盐损伤中XBP1的保护机制（特定的目标＃3）。 尽管该提案侧重于肝XBP1，但长期目标是开发一系列研究，以确定可以作为治疗胆固醇肝脏疾病的治疗靶标的UPR信号通路。 该建议利用了最先进的小鼠遗传学，分子生物学和脂质生化技术来进一步了解XBP1在胆汁盐损伤和胆汁淤积中的保护作用。 研究确定XBP1信号通路作用及其对胆汁盐诱导的肝损伤的作用的研究可能会确定一种新的途径和药物发育的潜在靶标，以治疗胆固性肝疾病。 公共卫生相关性：胆汁淤积性肝脏疾病是造成进行性肝脏疾病的常见原因，可能导致肝硬化和肝衰竭。不幸的是，胆汁淤积性肝病的医疗疗法很少。我们将研究胆汁在肝损伤中的作用， 名为XBP1的肝蛋白的机理和保护作用在防止肝胆汁盐损伤中。