Role of the NCoR corepressor complex in the development of insulin resistance

NCoR 辅阻遏物复合物在胰岛素抵抗发展中的作用

基本信息

批准号：
8149970
负责人：
VALENTINA PERISSI
金额：
$ 24.65万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-25 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8149970
关键词：
Adipocytes Award Binding Biochemical Biological Assay Cells Characteristics Chemicals Complex Cytoplasm Data Defect Development Diabetes Mellitus Down-Regulation Enzymes Excision Future GPS2 gene GTP-Binding Proteins Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Goals Grant Human Inflammation Inflammatory Inflammatory Response Insulin Insulin Resistance Insulin Signaling Pathway Knockout Mice Knowledge Lead Light Link Location MAPK8 gene Mediating Metabolic Diseases Molecular NF-kappa B Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nuclear Receptors Obesity Pathway interactions Phase Phenotype Phosphorylation Phosphotransferases Physiological Play Principal Investigator Process Production Progress Reports Protein Kinase Proteins Reactive Oxygen Species Recruitment Activity Regulation Regulatory Element Research Role Series Serine Signal Transduction Small Interfering RNA Stimulus Stress Testing Transcription Repressor/Corepressor Transcriptional Activation Transcriptional Regulation Ubiquitin-Conjugating Enzymes Update base blood glucose regulation cofactor diabetic genome-wide improved in vivo in vivo Model inhibitor/antagonist insulin signaling mouse model novel overexpression programs promoter research study response transcription factor

项目摘要

PROGRESS REPORT AND UPDATED RESEARCH PLAN The main goal of this grant was to investigate the role of a transcriptional cofactor, GPS2, and its novel interacting partner, NEURL4/KIAA1787, in obesity-associated inflammatory responses and in the development of insulin resistance. Our original hypothesis was that these two proteins could play a key inhibitory role during the physiological response to insuHn signaling by keeping the NFKB and APi signaling network under negative control in the absence of stimulatory signals. The loss or downregulation of such inhibition may participate in the development of obesity-induced insulin resistance. Three Specific Aims were proposed: i) To define GPS2-dependent gene networks in adipocytes; ii) To investigate the molecular mechanism of GPS2 and KIAA1787 functions in inhibiting JNK-mediated signaling and regulating transcriptional activation mediated by NFKB and APi transcription factors; iii) To test in vivo whether GPS2 and KIAA1787 are relevant for the development of insulin resistance by creating null mice models. Here, for each Aim, I will discuss the progresses made during the K99 phase of the award and describe the future experiments as the original plans have been updated in light ofthe current results.

进展报告和更新的研究计划该资助的主要目标是研究转录辅助因子 GPS2 及其新型相互作用伙伴 NEURL4/KIAA1787 在肥胖相关炎症反应和胰岛素抵抗发展中的作用。我们最初的假设是，这两种蛋白可以在胰岛素信号传导的生理反应过程中发挥关键的抑制作用，通过在没有刺激信号的情况下将 NFKB 和 APi 信号网络置于负控制之下。这种抑制作用的丧失或下调可能参与肥胖诱导的胰岛素抵抗的发展。提出了三个具体目标： i) 定义脂肪细胞中依赖 GPS2 的基因网络； ii) 研究GPS2和KIAA1787抑制JNK介导的信号传导以及调节NFKB和APi转录因子介导的转录激活的分子机制； iii) 通过创建无效小鼠模型来体内测试 GPS2 和 KIAA1787 是否与胰岛素抵抗的发展相关。在这里，对于每个目标，我将讨论在奖励的 K99 阶段取得的进展，并描述未来的实验，因为原始计划已根据当前结果进行了更新。