Repressor-PPAR Interactions in Inflammation and Atherosclerosis

描述（由申请人提供）：动脉粥样硬化是美国的主要死亡原因，现在被广泛认为是一种发生在动脉壁内的慢性炎症性疾病。巨噬细胞是与致动脉粥样硬化性炎症有关的关键先天免疫细胞类型，这是一种主要由转录改变驱动的病理生理学。过去二十年的工作已经确定了通过细胞表面toll样和细胞因子受体启动的途径，其最终导致NF-κ B、AP 1和Stat蛋白的激活以及编码细胞因子、趋化因子和基质重塑酶的促炎基因的随后转录激活。然而，促炎基因减弱的手段和机制仍然知之甚少。过氧化物酶体增殖物激活受体（PPARs）是一种脂质敏感核受体，代表了营养、代谢和炎症之间的联系。重要的是，两种PPAR同种型在巨噬细胞中表达，PPARg和PPARd，并且这些受体中的每一种的合成激活剂在小鼠模型中具有抗炎和抗动脉粥样硬化作用。关于这些治疗作用的分子机制知之甚少，但现有数据表明，与阻遏蛋白NCoR和BCL 6的相互作用可能是其抗炎作用的核心。该提议的一个中心假设是炎症可以在转录水平上由PPARs及其阻遏物调节。我们将阐明三个组成部分的过氧化物酶体增殖物激活受体阻遏物复合物，包括BCL 6，SMRT，和NCoR在巨噬细胞引起的炎症，动脉粥样硬化，和过氧化物酶体增殖物激活受体抗炎控制的作用。实验将利用独特的小鼠敲除，敲入和敲低模型，并利用生物化学，分子和生理学方法。相关性（参见说明）：这些研究将进一步加深我们对炎症和动脉粥样硬化的理解，重点是PPARd发挥其抗炎作用的机制。这项工作的见解可以确定新型抗炎药物或下一代PPAR化合物的靶点，这些药物旨在改善动脉粥样硬化和其他炎症性疾病的治疗。

DESCRIPTION (provided by applicant): Atherosclerosis is the leading cause of death in the United States and is now widely recognized as a chronic inflammatory disease occurring within the artery wall. The macrophage is the key innate immune cell type implicated in atherogenic inflammation, a pathophysiology largely driven by alterations in transcription. Work over the past two decades has identified pathways initiated through cell surface toll-like and cytokine receptors which culminate in the activation of NF-kB, AP1, and Stat proteins and subsequent transcriptional activation of pro-inflammatory genes encoding cytokines, chemokines, and matrix remodeling enzymes. The means and mechanisms by which pro-inflammatory genes are attenuated, however, remain poorly understood. Peroxisome proliferator activated receptors (PPARs) are lipid-sensing nuclear receptors and represent a nexus between nutrition, metabolism, and inflammation. Importantly, two PPAR isotypes are expressed in macrophages, PPARg and PPARd, and synthetic activators of each of these receptors are anti-inflammatory and anti-atherosclerotic in mouse models. Little is known about the molecular mechanisms underlying these therapeutic effects, but existing data suggest that interactions with the represser proteins NCoR and BCL6 may be central to their anti-inflammatory actions. A central hypothesis of this proposal is that inflammation can be modulated at the transcriptional level by PPARs and their repressors. We will elucidate roles for three components of the PPAR repressor complex, including BCL6, SMRT, and NCoR in macrophage- elicited inflammation, atherogenesis, and PPAR anti-inflammatory control. Experiments will take advantage of unique mouse knockout, knock-in, and knock-down models and utilize biochemical, molecular, and physiologic approaches. RELEVANCE (See instructions): These studies will further our understanding of inflammation and atherosclerosis, focusing on the mechanisms by which PPARd exerts its anti-inflammatory effects. Insights from this work may identify targets for new types of anti-inflammatory drugs or next-generation PPAR compounds designed to improve the treatment of atherosclerosis and other inflammatory diseases.