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

描述（由候选人提供）： GPS 2最近被报道为转录中的主要阻遏物复合物之一，NCoR/SMRT核受体辅阻遏物复合物的内在组分。虽然GPS 2的特异性功能大多是未知的，但我们的初步数据显示，GPS 2是防止包括AP 1和NF κ B在内的几种转录因子的组成性激活所必需的。因为GPS 2最初是作为组成性G蛋白信号传导的抑制剂在酵母中分离的，并且它显示出抑制响应于TNF α的JNK活性，所以我们的假设是GPS 2和新鉴定的GPS 2相互作用蛋白KIAA 1787，是防止JNK和IKK激酶途径的不希望的激活所需的内源性抑制剂，因此用于保持在严格控制下的大的前体蛋白，已知在肥胖和随后的胰岛素抵抗发展过程中激活的炎性转录程序。我们提出了3个具体目标：i）结合微阵列和ChlP芯片技术定义脂肪细胞中GPS 2依赖性基因网络; ii）研究GPS 2和KIAA 1787在调节NFkB和AP 1途径中功能的分子机制; iii）生成动物模型来解决体内GPS 2和KIAA 1787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有很强的背景，以前曾研究过核受体，NFkB和AP 1转录因子的其他转录辅助调节因子的作用，该提案旨在将基础研究与翻译方法相结合，以研究这些新因子在胰岛素抵抗和II型糖尿病中的作用。申办方，M.G.博士Rosenfeld和共同申办者J.OIefsky博士将负责实验设计和项目开发，并为候选人在糖尿病和炎症研究领域实现独立提供科学支持。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，其发病率预计将呈指数级增长，特别是在年轻人中。肥胖影响着近三分之一的美国人口，现在与胰岛素抵抗的发展及其发展为糖尿病密切相关。更好地表征炎症途径如何生理调节的分子基础对于开发新的治疗方法至关重要。

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.