PROJ 4: PHYSIOLOGICAL FUNCTION OF NUCLEAR RECEPTORS IN CHOLESTATIC LIVER DISEASE

项目 4：核受体在胆汁淤积性肝病中的生理功能

• 批准号: 7610775
• 负责人: Bryan L Copple
• 金额: $ 22.65万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610775
• 关键词: Animals; Bile Acid Biosynthesis Pathway; Bile Acids; Cholestasis; Computer Retrieval of Information on Scientific Projects Database; Drug Metabolic Detoxication; Excretory function; Funding; Gene Expression; Goals; Grant; Hepatocyte; Homeostasis; Injury; Institution; Liver; Liver diseases; Mus; Nuclear Receptors; Pathway interactions; Physiological; Proteins; Research; Research Personnel; Resources; Retinoid X Receptor alpha; Role; Source; Toxic effect; United States National Institutes of Health; base; constitutive androstane receptor; feeding; insight; pregnane X receptor; receptor; receptor function; uptake

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall goal of this proposal is to determine whether the nuclear receptors farnesoid-X-receptor (FXR), pregnane-X-receptor (PXR), constitutive androstane receptor (CAR), and retinoid-X-receptor alpha (RXRa) protect the liver during cholestatic liver disease. The main hypothesis is that FXR, PXR, CAR, and RXRa protect the liver during cholestatic liver disease by regulating bile-acid synthesis, transport, and detoxification. Cholestatic liver disease arises when excretion of bile acids from the liver is interrupted. This causes toxic bile acids to accumulate in liver, which produces hepatocyte injury. Recent studies have identified several nuclear receptors expressed by hepatocytes that regulate bile acid homeostasis, including FXR, PXR, CAR, and RXRa. When activated, these nuclear receptors regulate expression of genes in hepatocytes that encode for proteins that reduce bile-acid uptake and synthesis, as well as increase bile-acid excretion and detoxification. Studies have shown that some of these nuclear receptors are important for regulating bile-acid toxicity in mice fed toxic quantities of bile acids. However, it is not known whether these nuclear receptors function similarly and reduce bile acid toxicity during cholestasis. This forms the basis of this proposal, which will examine the physiological role of each of these nuclear receptors in cholestatic liver disease by systematically determining whether liver injury and bile-acid synthesis, transport, and detoxification are enhanced, reduced, or unaffected in nuclear receptor-null animals with different types of cholestatic liver disease. The studies in this proposal will not only provide important information about the physiological function of each nuclear receptor in cholestasis, but will also provide important insight into whether modulation of these pathways might be beneficial for the treatment of cholestatic liver disease.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该提案的总体目标是确定核受体法尼醇-X-受体（FXR）、孕烷-X-受体（PXR）、组成型雄甾烷受体（CAR）和类维生素A-X-受体α（RXRa）是否保护胆汁淤积性肝病期间的肝脏。主要假设是 FXR、PXR、CAR 和 RXRa 在胆汁淤积性肝病期间通过调节胆汁酸合成、运输和解毒来保护肝脏。当肝脏的胆汁酸排泄中断时，就会出现胆汁淤积性肝病。这会导致有毒胆汁酸在肝脏中积聚，从而造成肝细胞损伤。最近的研究发现了肝细胞表达的几种调节胆汁酸稳态的核受体，包括 FXR、PXR、CAR 和 RXRa。当激活时，这些核受体调节肝细胞中编码蛋白质的基因表达，这些蛋白质可减少胆汁酸的摄取和合成，并增加胆汁酸的排泄和解毒。研究表明，其中一些核受体对于调节饲喂有毒量胆汁酸的小鼠的胆汁酸毒性很重要。然而，尚不清楚这些核受体是否具有相似的功能并在胆汁淤积期间减少胆汁酸毒性。这构成了该提案的基础，该提案将通过系统地确定核受体中的肝损伤和胆汁酸合成、转运和解毒是否增强、减少或不受影响来检查每种核受体在胆汁淤积性肝病中的生理作用-患有不同类型胆汁淤积性肝病的无效动物。该提案中的研究不仅将提供有关胆汁淤积中每种核受体的生理功能的重要信息，还将提供有关这些途径的调节是否可能有益于胆汁淤积性肝病的治疗的重要见解。