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

巨噬细胞中 PPAR^依赖性基因网络的功能表征。

• 批准号: 8355985
• 负责人: Christopher K Glass
• 金额: $ 41.77万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8355985
• 关键词: 2,4-thiazolidinedione; 3-Dimensional; Actins; Adipocytes; Adipose tissue; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Cell Nucleus; Chromatin; Collaborations; Complement; Complex; Development; Diet; Environment; Evaluation; Exhibits; Fatty Acids; Fatty acid glycerol esters; Future; Gene Expression; Gene Targeting; Genes; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Interferons; Interleukin-4; Investigation; Ligands; Location; Macrophage Activation; Maintenance; Mediating; Methods; Molecular; Movement; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Receptors; Obesity; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phenotype; Physiological; Play; Polyunsaturated Fatty Acids; Production; RNA; Regulation; Repression; Role; Shapes; Signal Pathway; Signal Transduction; TLR4 gene; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Thiazolidinediones; Tissues; Toll-like receptors; Transcript; base; blood glucose regulation; cytokine; diabetic; genome wide association study; genome-wide; improved; in vivo; innovation; insulin sensitivity; long chain fatty acid; macrophage; novel strategies; palmitoleic acid; prevent; receptor; response

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.

项目3将研究巨噬细胞中影响胰岛素抵抗的转录网络。我们建议的研究将主要集中在了解巨噬细胞中NCoR共抑制物缺失带来的意想不到的生理和细胞后果，以及降低巨噬细胞PPARy促进正常血糖稳态和胰岛素增敏效应的分子机制。 噻唑烷二酮类(TZDS)。这些研究将补充项目1和项目2中进行的研究，以提高我们对推动胰岛素抵抗发展的中央致病机制的理解。Speciflc Aim 1将测试这一假设，即巨噬细胞特异性干扰NCoR导致胰岛素敏感性增强，这是由于LXR和/或PPARy靶基因的抑制导致抗炎脂肪酸的产生。这些研究有可能确定巨噬细胞影响胰岛素抵抗的一条全新的途径，该途径可能可用于治疗干预。特殊目标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PPARy在整个基因组中的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，并通过胰岛素增敏的PPARy配体恢复。这些研究将利用新的体内方法来确定脂肪组织中巨噬细胞特异性PPAR的位置和功能，而不需要广泛的纯化 方法：研究方法。具体目标3的研究将与项目2合作进行，以验证以下假设：交替的巨噬细胞激活改变染色质相互作用体，从而促进依赖PPARy的基因表达，并拮抗依赖TLR4的基因表达。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内的三维水平上整合的。