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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本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）、组成型雄烷受体（CAR）和维甲酸-X-受体α（RXRa）是否在胆汁淤积性肝病期间保护肝脏。主要假设是FXR、PXR、CAR和RXRa通过调节胆汁酸合成、转运和解毒来保护胆汁淤积性肝病期间的肝脏。胆汁淤积性肝病是指胆汁酸从肝脏中的排泄中断。这导致毒性胆汁酸在肝脏中积累，从而产生肝细胞损伤。最近的研究已经确定了几种由肝细胞表达的调节胆汁酸稳态的核受体，包括FXR、PXR、CAR和RXR α。当被激活时，这些核受体调节肝细胞中基因的表达，这些基因编码减少胆汁酸摄取和合成的蛋白质，以及增加胆汁酸排泄和解毒。研究表明，这些核受体中的一些对于调节喂食毒性量胆汁酸的小鼠的胆汁酸毒性是重要的。然而，尚不清楚这些核受体是否具有相似的功能，并在胆汁淤积期间降低胆汁酸毒性。这构成了本提案的基础，该提案将通过系统地确定在具有不同类型胆汁淤积性肝病的核受体缺失动物中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这些核受体中的每一种在胆汁淤积性肝病中的生理作用。本提案中的研究不仅将提供关于胆汁淤积中每个核受体的生理功能的重要信息，而且还将提供重要的见解，以了解这些途径的调节是否可能有利于胆汁淤积性肝病的治疗。