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

• 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
• 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

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.

进展报告和补充研究报告 这项资助的主要目标是研究转录辅因子GPS 2及其新型相互作用伴侣NEURL 4/KIAA 1787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，这两种蛋白质可以通过在没有刺激信号的情况下将NF κ B和API信号网络保持在负控制下，在对胰岛素信号的生理反应期间发挥关键的抑制作用。这种抑制的丧失或下调可能参与肥胖诱导的胰岛素抵抗的发展。提出了三个具体目的：i）定义脂肪细胞中的GPS 2依赖性基因网络; ii）研究GPS 2和KIAA 1787在抑制JNK介导的信号传导和调节NF κ B和API转录因子介导的转录激活中的分子机制; iii）通过创建无效小鼠模型在体内测试GPS 2和KIAA 1787是否与胰岛素抵抗的发展相关。 在这里，对于每一个目标，我将讨论在K99阶段所取得的进展，并描述未来的实验，因为最初的计划已经根据目前的结果进行了更新。