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:8446092
- 负责人:
- 金额:$ 33.6万
- 依托单位:
- 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 2016-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAmericanApplications GrantsAttenuatedBinding ProteinsBiochemicalBoxingCellular biologyCholestasisCholic AcidsCirrhosisDataDevelopmentDiseaseDisease ProgressionFeedbackGeneticGoalsHepaticHepatotoxicityIn VitroInjuryInvestigationLeadLifeLipid BiochemistryLipidsLiverLiver FailureLiver diseasesMediatingMedicalMetabolismMolecular BiologyMusNamesNatural HistoryPathogenesisPathway interactionsPharmaceutical PreparationsPredispositionPrimary biliary cirrhosisProteinsRNA SplicingResearchRoleSignal PathwayTechniquesTherapeuticToxic effectUnited StatesUrsodeoxycholic Acidattenuationbile saltsdietary supplementsdrug developmentendoplasmic reticulum stressfeedinggene synthesisin vivoliver transplantationnovelpreventprimary sclerosing cholangitisprotective effectresponsetherapeutic target
项目摘要
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):胆汁淤积性肝病是美国进行性肝病的非常普遍的原因,并且是肝移植的常见适应症。不幸的是,目前的药物疗法无法治愈,也可能无法阻止疾病进展。在过去的十年中,未折叠蛋白反应(UPR)是一种对内质网(ER)应激的适应性细胞反应,与许多肝脏疾病的发病机制有关。然而,UPR 在肝胆汁盐毒性和胆汁淤积性肝病中的作用仍有待探索。 X-box 结合蛋白 1 剪接 (XBP1s) 是 UPR 的关键调节分子,我们的初步数据表明它可以防止胆汁盐损伤。该提议的中心假设是,XBP1s 在胆汁淤积期间对活体具有保护作用,并且 XBP1s 的肝脏表达减弱会导致肝脏胆汁盐转运蛋白的表达减少,并增加对肝胆汁盐肝损伤的易感性。 因此,在本提案中,我们将给小鼠喂食补充胆酸的饮食,并确定 XBP1 和下游靶标在肝胆汁盐损伤中的作用(具体目标#1)。 CYP7a1是胆汁盐合成的限速步骤,抑制CYP7a1的表达和活性可以作为负反馈机制来减少胆汁盐池。我们提供的初步数据表明肝脏 UPR 的激活显着降低了表达
肝脏 CYP7a1 的变化,可能是通过 XBP1s 介导的途径。因此,我们将确定未折叠蛋白反应和 XBP1 抑制肝脏 Cyp7a1 表达、功能和胆汁盐合成(具体目标 #2)。 最后,为了直接确定肝脏 XBP1 表达的减弱会增加对胆汁盐肝毒性的易感性,我们将开发具有肝脏特异性 XBP1 缺失的转基因小鼠。我们将开发肝脏特异性 XBP1(-/-) 小鼠,以确认 XBP1 在肝胆汁盐损伤中的保护作用并明确其保护机制(具体目标#3)。 虽然该提案重点关注肝脏 XBP1,但长期目标是开展一系列研究,以确定可作为治疗胆汁淤积性肝病的治疗靶点的 UPR 信号通路。 该提案利用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。 确定 XBP1s 信号通路的作用及其对胆汁盐诱导的肝损伤的影响的研究可能会确定治疗胆汁淤积性肝病药物开发的新途径和潜在靶点。
公共卫生相关性:胆汁淤积性肝病是进行性肝病的常见原因,可导致肝硬化和肝衰竭。不幸的是,针对胆汁淤积性肝病的药物疗法很少。我们将研究胆汁盐在肝损伤中的作用,以及
一种名为 XBP1s 的肝蛋白预防肝胆汁盐损伤的机制和保护作用。
项目成果
期刊论文数量(0)
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Richard M Green其他文献
Richard M Green的其他文献
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{{ truncateString('Richard M Green', 18)}}的其他基金
Ex-vivo bioengineered technology to unravel dysfunction due to non-alcoholic steatohepatitis (NASH)
离体生物工程技术可解决非酒精性脂肪性肝炎 (NASH) 引起的功能障碍
- 批准号:
10744393 - 财政年份:2023
- 资助金额:
$ 33.6万 - 项目类别:
Molecular and Genetic Mechanisms of Fatty Liver Disease
脂肪肝的分子和遗传机制
- 批准号:
9135051 - 财政年份:2015
- 资助金额:
$ 33.6万 - 项目类别:
Molecular and Genetic Analysis of Murine Steatohepatitis
小鼠脂肪性肝炎的分子和遗传学分析
- 批准号:
7943027 - 财政年份:2009
- 资助金额:
$ 33.6万 - 项目类别:
Molecular and Genetic Analysis of Murine Steatohepatitis
小鼠脂肪性肝炎的分子和遗传学分析
- 批准号:
7740160 - 财政年份:2009
- 资助金额:
$ 33.6万 - 项目类别:
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