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

描述(由候选人提供)： 最近有报道称，GPS2是转录中的一个主要的抑制物复合体，即NCoR/SMRT核受体辅阻遏物复合体的内源性成分。虽然GPS2的特定功能大多尚不清楚，但我们的初步数据表明，GPS2是阻止包括AP1和NFkB在内的几个转录因子的结构性激活所必需的。由于GPS2最初是作为结构性G蛋白信号的抑制者从酵母中分离出来的，并且它被证明可以抑制JNK的活性以响应TNFa，我们的假设是GPS2和新发现的GPS2相互作用蛋白KIAA1787是内源性抑制物，需要防止JNK和IKK激酶途径的意外激活，从而使大的促炎转录程序处于严格控制之下，这些程序已知在肥胖和随后的胰岛素抵抗发展过程中被激活。我们提出了3个具体的目标：1)结合微阵列和ChlP芯片技术确定脂肪细胞中依赖GPS2的基因网络；2)研究GPS2和KIAA1787在NFkB和AP1通路调控中的分子机制；3)建立动物模型，在体内研究GPS2和KIAA1787与胰岛素抵抗发生的相关性。候选人佩里西博士在分子生物学方面有很强的背景，之前曾研究过核受体的其他转录协同调节因子NFkB和AP1转录因子的作用，这项提议的目的是将她之前的基础研究与翻译方法结合起来，研究这些新因子在胰岛素抵抗和II型糖尿病中的作用。发起人M.G.Rosenfeld博士和联合发起人J.OIefsky博士将忽略该项目的实验设计和开发，并将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，影响着西方世界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。肥胖正影响着近三分之一的美国人口，现在它与胰岛素抵抗的发展及其发展成糖尿病密切相关。更好地描述炎症通路是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.