Metabolic Regulation by the Nuclear Receptor CAR

描述（由申请人提供）：在自然环境中，生物体经常暴露于各种潜在有毒的外来化合物或异生物质。生物体还产生必须代谢的内源性有毒化合物。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毒剂的特性和浓度变化很快，因此其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是对外源性挑战的反应的中心调节剂。此外，PXR最近与胆汁酸代谢有关，初步结果表明CAR是胆红素清除的中心调节剂。因此，该提议基于以下假设：CAR是对外源性和内源性化合物的特异性代谢反应的关键调节剂。其长期目标是了解CAR的这些调节功能及其与PXR和其他代谢调节因子的整合。具体目标是：1）使用基因敲除小鼠模型来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）使用基因敲除小鼠来确定CAR在对对肝脏代谢具有重要影响的异生物质化合物的应答中的作用，包括非处方镇痛剂对乙酰氨基酚和植物来源的保肝药水飞蓟宾;和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。异生物质反应在有趣的方面类似于免疫反应。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节的理解的增加导致了对病理过程的重要见解，也导致了新的治疗途径。我们相信，更好地了解异生素反应可能会产生类似的好处。

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.