Functional Characterization of PPAR^-Dependent Gene Networks in Macrophages.

（附件）： 项目3将研究巨噬细胞中影响胰岛素抵抗的转录网络。我们 拟议的研究将主要集中在了解意想不到的生理和细胞后果 在巨噬细胞中删除NCoR辅阻遏物，并定义分子机制， 巨噬细胞PPARy有助于正常葡萄糖稳态和胰岛素增敏作用 噻唑烷二酮类（TZDs）。这些调查将补充项目1和项目2中进行的研究。 2提高我们对驱动胰岛素发展的中枢致病机制的理解 阻力特异性目的1将检验巨噬细胞特异性NCor破坏导致 由于驱动胰岛素产生的LXR和/或PPARy靶基因的去阻遏而增强的胰岛素敏感性 抗炎脂肪酸。这些研究有可能通过以下方式确定一种全新的途径： 巨噬细胞影响胰岛素抵抗，这可能是可行的治疗干预。具体 目的2将研究巨噬细胞PPARy促进正常葡萄糖稳态的机制 和TZD的抗糖尿病作用。我们将测试的假说，基因组范围内的位置和功能， PPARy在肥胖脂肪组织的脂肪组织巨噬细胞中受损，并通过 胰岛素致敏PPARy配体。这些研究将利用新的体内方法来确定 不需要广泛纯化的脂肪组织中巨噬细胞特异性过氧化物酶体增殖体激活受体的定位和功能 方法.具体目标3的研究将与项目2合作进行，以检验假设 巨噬细胞活化改变了染色质相互作用组， 基因表达和拮抗TLR 4依赖性基因表达。这些研究将测试一个新的概念 了解抗炎和促炎信号如何在三维水平上整合 在细胞核中。 相关性（见说明）： 这些研究对提高对中枢性致病的认识具有重要意义 推动胰岛素抵抗发展和塑造未来治疗方法的机制 预防和治疗2型糖尿病。

instrucUons): Project 3 will investigate transcriptional networks in macrophages that influence Insulin resistance. Our proposed studies will primarily focus on understanding unexpected physiological and cellular consequences of deletion of the NCoR co-repressor in macrophages and on deflning the molecular mechanisms by which macrophage PPARy contributes to normal glucose homeostasis and insulin sensitizing effects of thiazolidinediones (TZDs). These lines of investigation will complement studies performed in Projects 1 and 2 to improve our understanding of central pathogenic mechanisms that drive the development of insulin resistance. Speciflc Aim 1 will test the hypothesis that macrophage-speciflc disruption of NCor results in enhanced insulin sensitivity due to de-repression of LXR and/or PPARy target genes that drive production of anti-inflammatory fatty acids. These studies have the potential to identify a fundamentally new pathway by which macrophages influence insulin resistance that may be amendable to therapeutic intervention. Specific Aim 2 will investigate mechanisms by which macrophage PPARy contributes to normal glucose homeostasis and anti-diabetic effects of TZDs. We will test the hyothesis that the genome-wide locations and functions of PPARy are compromised in adipose tissue macrophages of obese adipose tissue and are restored by insulin-sensitizing PPARy ligands. These studies will make use of new in vivo approaches for determining macrophage-specific PPAR location and function in adipose tissue that do not require extensive purification methods. Studies in Specific Aim 3 will be performed in collaboration with Project 2 to test the hypothesis that alternative macrophage activation alters the chromatin interactome so as to facilitate PPARy-dependent gene expression and antagonize TLR4-dependent gene expression. These studies will test a new concept for understanding how anti-inflammatory and pro-inflammatory signals are integrated at a 3 dimensional level in the nucleus. RELEVANCE (See instmctions): The proposed studies will be of signiflcance in improving our understanding of central pathogenic mechanisms that drive the development of insulin resistance and in shaping future therapeutic approaches to prevent and treat type 2 diabetes.