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

项目3将研究巨噬细胞中影响胰岛素抵抗的转录网络。我们的 拟议的研究将主要集中于了解意想不到的生理和细胞后果 巨噬细胞中NCoR共抑制子的缺失及其分子机制的研究 巨噬细胞PPARy促进正常血糖稳态及胰岛素增敏作用 噻唑烷二酮类(TZDS)。这些调查路线将补充项目1和项目1中进行的研究 2增进我们对推动胰岛素发展的中枢致病机制的了解 抵抗。Speciflc Aim 1将测试巨噬细胞特异性破坏NCoR导致 抑制LXR和/或PPARy靶基因导致的胰岛素敏感性增强 抗炎脂肪酸。这些研究有可能通过以下方式确定一条全新的途径 哪些巨噬细胞影响胰岛素抵抗，这可能是可用于治疗干预的。特定的 Aim 2将研究巨噬细胞PPARy促进正常血糖稳态的机制 以及TZDS的抗糖尿病作用。我们将测试全基因组的位置和功能 PPARy在肥胖脂肪组织的巨噬细胞中受损，并通过 胰岛素增敏PPARy配体。这些研究将利用新的体内方法来确定 不需要大量纯化的脂肪组织中巨噬细胞特异性PPAR的定位和功能 方法：研究方法。具体目标3的研究将与项目2合作进行，以检验假设 巨噬细胞的交替激活改变了染色质相互作用体，从而促进了PPARy依赖 基因表达，拮抗TLR4依赖的基因表达。这些研究将测试一个新的概念 为了了解抗炎和促炎信号是如何在三维水平上整合的 在原子核中。 相关性(请参阅说明)： 所提出的研究将对提高我们对中枢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。

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.