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：
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
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/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

项目摘要

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.

最近报道称 GPS2 是一种主要抑制复合物的内在成分转录，NCoR/SMRT 核受体辅阻遏物复合物。虽然 GPS2 的具体功能是大部分未知，我们的初步数据表明 GPS2 是防止本构激活所必需的多种转录因子，包括 AP1 和 NFkB。因为 GPS2 最初是在酵母中作为组成型 G 蛋白信号传导的抑制剂，并且它被证明可以抑制响应 TNFa 的 JNK 活性，我们的假设是 GPS2 和新发现的 GPS2 相互作用蛋白 KIAA1787 是内源性的防止 JNK 和 IKK 激酶途径意外激活所需的抑制剂，因此严格控制已知被激活的大型促炎症转录程序肥胖期间以及随之而来的胰岛素抵抗的发展。我们提出 3 个具体目标： i) 定义结合微阵列和 ChlP 芯片技术，脂肪细胞中 GPS2 依赖性基因网络； ii) 研究 GPS2 和 KIAA1787 调节 NFkB 功能的分子机制和 AP1 途径； iii) 生成动物模型以解决体内 GPS2 和 KIAA1787 的相关性胰岛素抵抗的发展。候选人Perissi博士拥有深厚的分子生物学背景之前研究过核受体、NFkB 和其他转录共调节因子的作用 AP1 转录因子和本提案旨在将已表征的基础研究结合起来她之前使用转化方法研究这些新因素在胰岛素中的作用的经验抵抗力和II型糖尿病。发起人 M.G.Rosenfeld 博士和联合发起人 J.OIefsky 博士将负责项目的实验设计和开发，为研究提供科学支持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% 的人口预计其发病率将呈指数级增长，尤其是在年轻人中。肥胖，即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进展为糖尿病。更好地表征分子基础炎症途径的生理调节对于开发新的治疗方法至关重要。