PPARs in Atherosclerosis and Immunity

描述(申请人提供)：过氧化体增殖物激活受体是脂类激活的核受体，它与维甲酸X受体异源二聚，调节目标基因启动子的转录。过去十年的工作已经确定了PPAR在调节脂肪和葡萄糖代谢中的多种角色。此外，PPARg和PPARd在巨噬细胞中表达，似乎在动脉粥样硬化中起作用。我计划通过三个系列的实验进一步研究PPARg和PPARd在巨噬细胞生物学和动脉粥样硬化中的作用。第一组实验将探索PPARg介导的动脉粥样硬化保护的机制。具体地说，我将测试这些效应是否依赖于一类相关的核受体，即肝X受体。在第二组研究中，我将检验合成的PPARd激动剂对动脉粥样硬化的影响。我已经用这种药物进行了一项初步研究，它们似乎在小鼠身上具有动脉粥样硬化保护作用。在第三系列实验中，我计划通过用一组不同的病原体攻击PPAR缺陷小鼠来确定PPARg和PPARd在急性免疫反应中的作用。这样的见解也可能与PPAR在动脉粥样硬化中的炎症作用有关。

DESCRIPTION (provided by applicant): Peroxisome proliferator-activated receptors are lipid-activated nuclear receptors that heterodimerize with retinoid X receptors to modulate transcription at target gene promoters. Work over the past decade has defined multiple roles for the PPARs in the regulation of lipid and glucose metabolism. Additionally, PPARg and PPARd are expressed in macrophages and appear to have roles in atherosclerosis. I plan to further examine the functions of PPARg and PPARd in macrophage biology and atherosclerosis with three series of experiments. The first set of experiments will explore the mechanism underlying PPARg-mediated atheroprotection. Specifically, I will test whether these effects are dependent upon a related class of nuclear receptors, known as liver X receptors. In the second set of studies, I will examine the effects of synthetic PPARd agonists on atherosclerosis. I have already performed a pilot study with such drugs, and they appear to be atheroprotective in mice. In a third series of experiments, I plan to determine the roles of PPARg and PPARd in acute immune responses by challenging PPAR-deficient mice with a panel of different pathogens. Such insights may also be relevant to the inflammatory roles of PPARs in atherosclerosis.