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

基本信息

批准号：
8907298
负责人：
Evan D Rosen
金额：
$ 46.98万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/8907298
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 Glucocorticoid Receptor Glucocorticoids Goals Health Histones Human In Vitro Inflammation Insulin Insulin Resistance Insulin Resistance Pathway Knock-out Knowledge Life 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 Pathway interactions Peripheral Phenotype Phosphorylation Play Polycystic Ovary Syndrome Positioning Attribute Post-Translational Protein Processing Pregnancy Process Reactive Oxygen Species Resistance Role Sepsis Site Steroids Stimulus Stress Testing Therapeutic Thiazolidinediones Time Tissues Transgenic Organisms Translating Tumor Necrosis Factor-alpha Vitamin D3 Receptor Work base clinical phenotype comparative epigenomics improved in vivo insulin sensitivity insulin signaling loss of function mitochondrial dysfunction novel overexpression programs public health relevance receptor receptor binding transcription factor transcriptome sequencing

项目摘要

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（通过应用程序提供）：胰岛素抵抗是2型糖尿病的正弦量，肥胖症，脂肪营养不良，感染，类固醇使用，关键疾病以及各种其他疾病和伤害。长期以来，这是一个神秘的，有如此多的深层刺激都导致相同的临床表型。此外，大多数胰岛素抵抗的研究都被分配了细胞质，线粒体和与ER相关的途径的作用，例如有毒脂质中间体，氧化应激或ER应激。很少有研究集中在胰岛素抵抗的核机制上，多斯蒂特的有力证据表明必须发挥转录和表观遗传因素。我们已经在用地塞米松（DEX）或TNFα（TNF）处理的3T3-L1脂肪细胞中使用了胰岛素抵抗的比较模型来识别引起这种疾病的新型途径。综合转录，表观基因组和计算分析已确定两个核骑术受体很重要。 TNF介导的糖皮质激素受体（GR）作用和维生素D受体（VDR）。该建议将确定GR和VDR在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标。重要的是，它还将使用功能丧失方法在体内验证我们的发现。综上所述，该提案有可能表征具有固有治疗潜力的两种新型胰岛素抵抗途径。