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。我们提出的研究将主要集中在理解巨噬细胞中NCoR辅阻遏物缺失的意外生理和细胞后果，以及定义巨噬细胞PPARy有助于正常葡萄糖稳态和胰岛素增敏作用的分子机制。 噻唑烷二酮类（TZDs）。这些研究将补充项目1和2中的研究，以提高我们对推动胰岛素抵抗发展的中枢致病机制的理解。特异性目的1将检验以下假设：由于驱动抗炎脂肪酸产生的LXR和/或PPARy靶基因的去阻遏，NCor的巨噬细胞特异性破坏导致胰岛素敏感性增强。这些研究有可能确定一个全新的途径，巨噬细胞影响胰岛素抵抗，可能是可行的治疗干预。具体目标2将研究巨噬细胞PPARy有助于正常葡萄糖稳态的机制 和TZD的抗糖尿病作用。我们将检验这样的假设，即PPARy的全基因组位置和功能在肥胖脂肪组织的脂肪组织巨噬细胞中受到损害，并通过胰岛素增敏PPARy配体恢复。这些研究将利用新的体内方法来确定巨噬细胞特异性过氧化物酶体增殖体激活受体在脂肪组织中的位置和功能，而不需要广泛的纯化 方法.将与项目2合作开展特定目标3的研究，以检验替代性巨噬细胞活化改变染色质相互作用组以促进PPAR γ依赖性基因表达并拮抗TLR 4依赖性基因表达的假设。这些研究将测试一个新的概念 以了解抗炎和促炎信号是如何在细胞核的三维水平上整合的。

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.