Metabolic Regulation by the Nuclear Receptor CAR

描述(申请人提供)：在自然环境中，生物体不断地暴露在各种潜在有毒的外来化合物或异生物质中。生物体还会产生必须代谢的内源性有毒化合物。在哺乳动物中，这些物质包括胆红素和胆汁酸。由于外源性和内源性有毒物质的身份和浓度都可能迅速变化，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是异种生物挑战反应的中心调节因子。此外，PXR最近被认为与胆汁酸代谢有关，初步结果表明CAR是胆红素清除的中枢调节因子。因此，这一建议是基于这样的假设，即CAR是对外源和内源化合物的特定代谢反应的关键调节因子。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。其具体目的是：1)使用基因敲除小鼠模型来确定肝脏和其他组织中CAR和PXR的特定和重叠的靶基因，并确定CAR和PXR基因丢失的后果；2)使用基因敲除小鼠来确定CAR在对肝脏代谢有重要影响的外来化合物(包括非处方药对乙酰氨基酚和植物衍生的肝脏保护剂水飞蓟宾)的反应中的作用；以及3)确定CAR在调节内源性代谢途径，尤其是胆红素清除中的作用。异种生物反应在有趣的方面类似于免疫反应。例如，两者都对一系列极其不同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了解增加了对病理过程的重大洞察，也开辟了新的治疗途径。我们认为，更好地了解异种生物的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.