PROJ 4: PHYSIOLOGICAL FUNCTION OF NUCLEAR RECEPTORSIN CHOLESTATIC LIVER DIS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。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)、构成雄烷受体(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。主要的假说是FXR、PXR、CAR和RXRA通过调节胆汁酸的合成、运输和解毒来保护胆汁淤积性肝病期间的肝脏。胆汁淤积性肝病是当胆汁酸从肝脏排泄中断时发生的。这会导致有毒的胆汁酸在肝脏中积聚，从而产生肝细胞损伤。最近的研究已经确定了几种肝细胞表达的调节胆汁酸稳态的核受体，包括FXR、PXR、CAR和RXRA。当被激活时，这些核受体调节肝细胞中编码蛋白质的基因的表达，这些蛋白质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，这些核受体中的一些对于调节喂食有毒胆汁酸的小鼠的胆汁酸毒性是重要的。然而，目前尚不清楚这些核受体是否具有类似的功能，并在胆汁淤积期间减少胆汁酸的毒性。这构成了这一建议的基础，它将通过系统地确定不同类型胆汁淤积性肝病的核受体缺失动物的肝损伤和胆汁酸合成、运输和解毒是否增强、减少或不受影响，来研究这些核受体在胆汁淤积性肝病中的生理作用。这项研究不仅将提供有关胆汁淤积症中每个核受体的生理功能的重要信息，而且还将为调节这些途径是否有益于胆汁淤积性肝病的治疗提供重要的见解。

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.