A Causal Role for Nuclear Receptor Pathways in Insulin Resistance

核受体途径在胰岛素抵抗中的因果作用

• 批准号: 9212143
• 负责人: Evan D Rosen
• 金额: $ 45.75万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9212143
• 关键词: Acromegaly; Address; Adipocytes; Adipose tissue; Advanced Malignant Neoplasm; Affect; Aging; Animals; Area; Biological Models; Cells; ChIP-seq; Clinical; Complication; Computer Analysis; Critical Illness; Data; Development; Dexamethasone; Disease; Epigenetic Process; Functional disorder; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Glucocorticoid Receptor; Goals; Health; Histones; Human; In Vitro; Inflammation; Insulin; Insulin Resistance; Insulin Resistance Pathway; Knock-out; Knowledge; Ligands; Lipids; Lipodystrophy; MAPK14 gene; Mediating; Metabolic; Mitochondria; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Hormone Receptors; Nuclear Receptors; Obesity; Organism; Oxidative Stress; PPAR gamma; Participant; Pathogenesis; Pathogenicity; Pathway interactions; Peripheral; Phenotype; Phosphorylation; Play; Polycystic Ovary Syndrome; Positioning Attribute; Post-Translational Protein Processing; Pregnancy; Process; Reactive Oxygen Species; Resistance; Role; Sepsis; Short Interspersed Nucleotide Elements; Site; Steroids; Stimulus; Stress; TNF gene; Testing; Therapeutic; Thiazolidinediones; Time; Tissues; Transcription Coactivator; Transgenic Organisms; Translating; Vitamin D3 Receptor; Work; clinical phenotype; comparative; epigenomics; glucocorticoid-induced orphan receptor; improved; in vivo; insulin sensitivity; insulin signaling; loss of function; mitochondrial dysfunction; novel; overexpression; phosphoproteomics; public health relevance; receptor; receptor binding; transcription factor; transcriptome sequencing

 DESCRIPTION (provided by applicant): Insulin resistance is a sine qua non of Type 2 diabetes and a frequent complication of obesity, lipodystrophy, inflammation, steroid use, critical illness, and a variety of other conditions and insults. It has long been a mystery how so many profoundly different stimuli all result in the same clinical phenotype. Furthermore, most studies of insulin resistance have posited the action of cytoplasmic, mitochondrial, and ER-related pathways, such as toxic lipid intermediates, oxidative stress, or ER stress. Very few studies have focused on nuclear mechanisms of insulin resistance, despite strong evidence that transcriptional and epigenetic factors must be in play. We have used a comparative model of insulin resistance in 3T3-L1 adipocytes treated with dexamethasone (Dex) or TNFα (TNF) to identify novel pathways that cause this disorder. Integrated transcriptional, epigenomic, and computational analysis have identified two nuclear hormone receptors as important; TNF-mediated glucocorticoid receptor (GR) action and the vitamin D receptor (VDR). This proposal will identify the mechanisms by which the GR and VDR promote insulin resistance in both murine and human cells, and will identify the specific gene targets that mediate this effect. Importantly, it will also validate our findings in vivo, using both gain- and loss-of-function approaches. Taken together, this proposal has the potential to characterize two novel pathways of insulin resistance with inherent therapeutic potential.

 描述（由申请人提供）：胰岛素抵抗是 2 型糖尿病的必要条件，也是肥胖、脂肪营养不良、炎症、类固醇使用、危重病等常见并发症。 长期以来，许多截然不同的刺激都导致相同的临床表型一直是个谜。此外，大多数胰岛素抵抗的研究都假定细胞质、线粒体和 ER- 的作用。尽管有强有力的证据表明转录和表观遗传因素肯定在起作用，但很少有研究关注胰岛素抵抗的相关途径，例如有毒脂质中间体、氧化应激或内质网应激。在用地塞米松 (Dex) 或 TNFα (TNF) 处理的 3T3-L1 脂肪细胞可识别导致这种疾病的新途径。综合转录、表观基因组和计算分析已确定两种重要的核激素受体：TNF 介导的糖皮质激素受体 (GR)。该提案将确定 GR 和 VDR 在小鼠和人类细胞中促进胰岛素抵抗的机制，并将确定介导这种作用的特定基因靶点。重要的是，它还将使用功能获得和功能丧失方法在体内验证我们的发现，该提议有可能描述具有内在治疗潜力的胰岛素抵抗的两种新途径。