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: 8328959
• 负责人: VALENTINA PERISSI
• 金额: $ 24.28万
• 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/8328959
• 关键词: Address; Adipocytes; Affect; American; Animal Model; Basic Science; Binding; Biochemical; Biological Assay; Cells; Characteristics; Chemicals; Complex; Cytoplasm; Data; Defect; Development; Diabetes Mellitus; Down-Regulation; Enzymes; Excision; GPS2 gene; GTP-Binding Proteins; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Human; Incidence; Inflammation; Inflammatory; Insulin; Insulin Resistance; Insulin Signaling Pathway; Knockout Mice; Knowledge; Lead; Link; Location; MAPK8 gene; Mediating; Metabolic Diseases; Molecular; Molecular Biology; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nuclear Receptors; Obesity; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Play; Population; Principal Investigator; Process; Production; Protein Kinase; Proteins; Reactive Oxygen Species; Recruitment Activity; Regulation; Regulatory Element; Reporting; Research; Role; Series; Serine; Signal Transduction; Small Interfering RNA; Stimulus; Stress; Techniques; Testing; Transcription Factor AP-1; Transcription Repressor/Corepressor; Transcriptional Activation; Transcriptional Regulation; Ubiquitin-Conjugating Enzymes; Western World; Yeasts; base; blood glucose regulation; cofactor; design; diabetic; experience; genome-wide; improved; in vivo; in vivo Model; inhibitor/antagonist; insulin signaling; mouse model; novel; novel therapeutic intervention; overexpression; prevent; programs; promoter; research study; response; transcription factor; translational approach

GPS2 has been recently reported as an intrinsic component of one of the major represser complexes in transcription, the NCoR/SMRT nuclear receptor corepressor complex. While GPS2 specific functions are mostly unknown, our preliminary data show that GPS2 is required to prevent constitutive activation of several transcription factors, including AP1 and NFkB. Because GPS2 was originally isolated in yeast as a suppressor of constitutive G-protein signaling, and it was shown to inhibit JNK activity in response to TNFa, our hypothesis is that GPS2 and a newly identified GPS2-interacting protein, KIAA1787, are endogenous inhibitors required for preventing undesired activation of the JNK and IKK kinase pathways and therefore for keeping under tight control large pro-inflammatory transcription programs that are known to be activated during obesity and consequent development of insulin resistance. We propose 3 specific aims: i) to define GPS2-dependent gene networks in adipocytes with a combination of microarray and ChlP-chip techniques; ii) to investigate the molecular mechanism of GPS2 and KIAA1787 functions in the regulation of the NFkB and AP1 pathways; iii) to generate animal models to address in vivo GPS2 and KIAA1787 relevance for the development of insulin resistance. The candidate, Dr. Perissi, has a strong background in molecular biology and has previously investigated the role of other transcriptional coregulators of nuclear receptors, NFkB and AP1 transcription factors and with this proposal aims to combine the basic research that has characterized her previous experience with a translational approach to investigate the role of these novel factors in insulin resistance and type II diabetes. The Sponsor, Dr. M.G.Rosenfeld, and the co-Sponsor, Dr. J.OIefsky, will ovelook the experiments design and the development of the project and will provide the scientific support for the candidate to achieve independence in the field of diabetes and inflammation research. Type II diabetes is a complex metabolic disorder that affects between 6% and 20% of the population in the Western world and its incidence is expected to increase exponentially, especially among young people. Obesity, which is affecting almost a third of the American population, is now tightly link to the development of insulin resistance and its progression into diabetes. A better characterization of the molecular basis of how the inflammatory pathways are physiologically regulated is critical to develop novel therapeutic approaches.

GPS2最近被报道为一种主要的抑制物复合体的内在成分。 转录，NCoR/SMRT核受体辅阻遏子复合体。而GPS2的特定功能是 大部分未知，我们的初步数据显示，GPS2是必需的，以防止结构性激活 几种转录因子，包括AP1和NFkB。因为GPS2最初是从酵母中分离出来的 结构性G蛋白信号的抑制者，并被证明对TNFa的反应抑制JNK活性， 我们的假设是，GPS2和一种新发现的GPS2相互作用蛋白KIAA1787是内源性的 所需的抑制剂，以防止JNK和IKK激酶途径的异常激活，因此 严格控制已知被激活的大的促炎转录程序 在肥胖和随后的胰岛素抵抗的发展过程中。我们提出了三个具体目标：i)定义 结合微阵列和ChlP芯片技术研究脂肪细胞中依赖GPS2的基因网络； Ii)研究GPS2和KIAA1787在NFkB调控中的分子机制 和AP1途径；iii)建立动物模型，在体内解决GPS2和KIAA1787与 胰岛素抵抗的发展。候选人佩里西博士在分子生物学方面有很强的背景 之前已经研究了核受体的其他转录协同调节因子NFkB和NFkB的作用 AP1转录因子与本提案旨在结合已有的基础研究特征 她以前用翻译方法研究这些新因素在胰岛素中的作用的经验 耐药性和II型糖尿病。赞助商M.G.罗森菲尔德博士和联合赞助商J.OIefsky博士将 为该项目的实验设计和开发提供科学依据 在糖尿病和炎症研究领域实现独立的候选人。II型糖尿病 是一种复杂的代谢紊乱，影响西方世界6%至20%的人口 它的发病率预计将呈指数级增长，特别是在年轻人中。肥胖，这是 影响了近三分之一的美国人口，现在与胰岛素的发展密切相关 耐药性及其发展为糖尿病。更好地刻画分子基础是如何 炎症通路的生理调节是开发新的治疗方法的关键。