Repressor-PPAR Interactions in Inflammation and Atherosclerosis

炎症和动脉粥样硬化中阻遏蛋白-PPAR 的相互作用

基本信息

批准号：
8403977
负责人：
Grant D Barish
金额：
$ 12.35万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403977
关键词：
A Mouse Address Agonist Anti-Inflammatory Agents Anti-inflammatory Arteries Atherosclerosis Attenuated B-Cell Lymphoma 6 Protein BCL6 gene Biochemical Blood Vessels Bone Marrow Cause of Death Cell model Cell surface Cells Chronic Complex Cytokine Receptors Data Development Disease Enzymes Functional disorder Gap Junctions Gene Expression Profiling Genes Genetic Genetic Engineering Genetic Transcription Immune In Vitro Inflammation Inflammatory Instruction Interferons Knock-in Mouse Knock-out Knockout Mice Laboratories Lesion Ligands Lipids Mediating Mediator of activation protein Metabolism Modeling Molecular Molecular Genetics Mus Mutation NF-kappa B Nuclear Receptors Pathway interactions Peritoneal Macrophages Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Physiological Proteins Regulation Repression Role Smooth Muscle Myocytes System TLR4 gene Testing Therapeutic Effect Transcription Factor AP-1 Transcriptional Activation Transplantation United States Work atherogenesis base bone cell type cellular transduction chemokine chromatin immunoprecipitation cofactor cytokine design improved in vivo insight knock-down macrophage mouse model next generation novel novel therapeutics nuclear receptor co-repressor nutrition progenitor promoter protein complex receptor receptor binding research study retroviral transduction

项目摘要

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.

描述（由申请人提供）：动脉粥样硬化是美国的首要死因，目前被广泛认为是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化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 样受体和细胞因子受体启动的途径，最终导致 NF-kB、AP1 和 Stat 蛋白的激活以及随后编码细胞因子、趋化因子和基质的促炎基因的转录激活重塑酶。然而，人们对促炎基因减弱的方式和机制仍知之甚少。过氧化物酶体增殖物激活受体 (PPAR) 是脂质敏感核受体，代表营养、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，即 PPARg 和 PPARd，并且这些受体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。人们对这些治疗作用背后的分子机制知之甚少，但现有数据表明，与阻遏蛋白 NCoR 和 BCL6 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通过 PPAR 及其阻遏物在转录水平上进行调节。我们将阐明 PPAR 阻遏复合物的三个成分（包括 BCL6、SMRT 和 NCoR）在巨噬细胞引发的炎症、动脉粥样硬化和 PPAR 抗炎控制中的作用。实验将利用独特的小鼠敲除、敲入和敲低模型，并利用生化、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，重点关注 PPARd 发挥抗炎作用的机制。这项工作的见解可能会确定新型抗炎药或下一代 PPAR 化合物的靶标，旨在改善动脉粥样硬化和其他炎症性疾病的治疗。