Metabolic Regulation by the Nuclear Receptor CAR

描述（由申请人提供）：在自然环境中，生物体不断暴露于各种潜在有毒的外来化合物或异种生物中。生物体也会产生内源性有毒化合物，这些化合物必须被代谢掉。在哺乳动物中，这些包括胆红素和胆汁酸。由于外源性和内源性有毒物质的特性和浓度可以迅速变化，因此它们的管理是一个复杂的问题，必须以灵活和动态的方式加以解决。核激素受体CAR和PXR是应对外源挑战的主要调节因子。此外，PXR最近与胆汁酸代谢有关，初步结果表明CAR是胆红素清除的中枢调节因子。因此，这一提议是基于CAR是对外源性和内源性化合物的特定代谢反应的关键调节因子的假设。其长期目标是了解CAR的这些调节功能，以及它们与PXR和其他代谢调节因子的整合。具体目的是：1)利用敲除小鼠模型鉴定肝脏和其他组织中CAR和PXR的特异性和重叠靶基因，并确定CAR和PXR基因缺失的后果；2)利用敲除小鼠确定CAR在对肝脏代谢有重要影响的外源化合物（包括非处方镇痛药对乙酰氨基酚和植物源肝保护剂水飞蓟宾）的应答中的作用；3)确定CAR在调节内源性代谢途径，特别是胆红素清除中的作用。这种异种反应与免疫反应有一些有趣的相似之处。例如，两者都对各种各样的潜在威胁作出具体和适当的反应。对免疫反应的复杂调控的理解增加，导致了对病理过程的重要见解，也带来了新的治疗途径。我们相信，更好地了解外源性反应可能会产生类似的益处。

DESCRIPTION (provided by applicant): In the natural environment, organisms are constantly exposed to a wide range of potentially toxic foreign compounds, or xenobiotics. Organisms also produce endogenous toxic compounds that must be metabolized. In mammals, these include bilirubin and bile acids. Because the identities and the concentrations of both exogenous and endogenous toxic agents can change quickly, their management is a complex problem that must be addressed in a flexible and dynamic manner. The nuclear hormone receptors CAR and PXR are central regulators of the response to xenobiotic challenges. In addition, PXR has recently been implicated in bile acid metabolism and preliminary results suggest that CAR is a central regulator of bilirubin clearance. Thus, this proposal is based on the hypothesis that CAR is a key regulator of specific metabolic responses to both exogenous and endogenous compounds. Its long-term goal is to understand these regulatory functions of CAR and their integration with those of PXR and other metabolic regulators. The specific aims are to: 1) use knockout mouse models to identify specific and overlapping target genes for CAR and PXR in liver and other tissues, and determine the consequences of the loss of both the CAR and PXR genes; 2) use knockout mice to define the role of CAR in the response to xenobiotic compounds with important effects on liver metabolism, including the over-the-counter analgesic acetaminophen and the plant-derived hepatoprotectant silybin; and 3) define the role of CAR in the regulation of endogenous metabolic pathways, particularly bilirubin clearance. The xenobiotic response resembles the immune response in interesting ways. For example, both produce specific and appropriate responses to an extremely diverse array of potential threats. Increased understanding of the complex regulation of immune responses has led to significant insights into pathological processes and also to new therapeutic avenues. We believe that a better understanding of the xenobiotic response may generate analogous benefits.