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：
7456334
负责人：
VALENTINA PERISSI
金额：
$ 8.59万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7456334
关键词：
2,4-thiazolidinedione Accounting Address Adipocytes Affect American Animal Model Anti-Inflammatory Agents Anti-inflammatory Apis Basic Science Binding Biochemical Biological Assay Characteristics Chemicals Complex Cytoplasm Data Defect Development Diabetes Mellitus Disruption Down-Regulation Drug usage Enzymes Excision GPS2 gene GTP-Binding Proteins Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Transcription Genome Human Incidence Inflammation Inflammatory Insulin Insulin Resistance Insulin Signaling Pathway Knockout Mice Knowledge Lead Link Location MAPK8 gene Mediating Metabolic Diseases Modeling Molecular Molecular Biology NF-kappa B 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 Protein Overexpression Proteins Reactive Oxygen Species Recruitment Activity Regulation Regulatory Element Reporting Research Research Personnel Resistance Role Series Serine Signal Pathway Signal Transduction Small Interfering RNA Stimulus Stress Techniques Testing Thiazolidinediones 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 human GPS2 protein improved in vivo in vivo Model inhibitor/antagonist insulin signaling mouse model novel novel therapeutics prevent programs promoter research study response transcription factor translational approach

项目摘要

DESCRIPTION (provided by candidate): GPS2 has been recently reported as an intrinsic component of one of the major repressor 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 overlook 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.

描述（由候选人提供）：最近，GPS2是转录中主要的阻遏物复合物之一，即NCOR/SMRT核受体核心体复合物的内在组成部分。虽然GPS2特定功能大多未知，但我们的初步数据表明，GPS2需要用于防止包括AP1和NFKB在内的几种转录因子的本构激活。因为GPS2作为组成型G蛋白信号的抑制剂在酵母中分离出来，并且显示出对TNFA响应响应TNFA的JNK活性的抑制，我们的假设是GPS2和新鉴定的GPS2相互作用的蛋白质是kiaa1787，因此可以预防无内在的INSEGINES，并在不认真的情况下进行了PenRye，并保留了jnk Iss Iss Iss Iss Incer Incer Iscek Isck，JNK KIN是JNK的，JNK KIN是JNK的，JNKEK是JNK的。控制大型促炎转录程序，这些程序已知在肥胖症中被激活并随之而来的胰岛素抵抗发展。我们提出了3个具体目的：i）定义依赖于微阵列和CHLP芯片技术的脂肪细胞中GPS2依赖的基因网络； ii）研究GPS2和KIAA1787的分子机制在NFKB和AP1途径的调节中起作用； iii）生成动物模型以解决体内GPS2和KIAA1787与胰岛素抵抗发展的相关性。候选人Perissi博士在分子生物学方面具有很强的背景，并先前已经研究了核受体，NFKB和AP1转录因子的其他转录键控因子的作用，并通过此提案旨在结合她以前的经验的基础研究，使她以前的经验以翻译方法来调查这些新颖因素在胰岛素抵抗和类型II糖尿病中的作用。赞助商M.G.博士罗森菲尔德（Rosenfeld）和共同赞助商J.Oiefsky博士将忽略实验设计和项目的发展，并将为候选人提供科学支持，以实现糖尿病和炎症研究领域的独立性。 II型糖尿病是一种复杂的代谢疾病，影响西方世界的6％至20％的人口，其发病率预计将成倍增加，尤其是在年轻人中。肥胖症几乎影响了美国人口的三分之一，现在与胰岛素抵抗的发展及其发展为糖尿病紧密联系。更好地表征炎症途径在生理调节中的分子基础对于开发新型治疗方法至关重要。