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

进度报告和最新研究计划 这项资助的主要目的是研究转录辅助因子GPS2及其新的相互作用伙伴NEURL4/KIAA1787在肥胖相关炎症反应和胰岛素抵抗发展中的作用。我们最初的假设是，在没有刺激信号的情况下，这两种蛋白可能通过使NFKB和API信号网络处于负向控制，在InsuHn信号的生理反应中发挥关键的抑制作用。这种抑制的缺失或下调可能参与了肥胖诱导的胰岛素抵抗的发展。我们提出了三个具体的目标：i)确定脂肪细胞中依赖GPS2的基因网络；ii)研究GPS2和KIAA1787抑制JNK介导的信号转导和调节NFKB和API转录因子介导的转录激活的分子机制；iii)通过建立空白小鼠模型，在体内测试GPS2和KIAA1787是否与胰岛素抵抗的发生有关。 在这里，对于每个目标，我将讨论在K99奖项阶段取得的进展，并描述未来的实验，因为最初的计划已经根据当前的结果进行了更新。

PROGRESS REPORT AND UPDATED RESEARCH PLAN The main goal of this grant was to investigate the role of a transcriptional cofactor, GPS2, and its novel interacting partner, NEURL4/KIAA1787, in obesity-associated inflammatory responses and in the development of insulin resistance. Our original hypothesis was that these two proteins could play a key inhibitory role during the physiological response to insuHn signaling by keeping the NFKB and APi signaling network under negative control in the absence of stimulatory signals. The loss or downregulation of such inhibition may participate in the development of obesity-induced insulin resistance. Three Specific Aims were proposed: i) To define GPS2-dependent gene networks in adipocytes; ii) To investigate the molecular mechanism of GPS2 and KIAA1787 functions in inhibiting JNK-mediated signaling and regulating transcriptional activation mediated by NFKB and APi transcription factors; iii) To test in vivo whether GPS2 and KIAA1787 are relevant for the development of insulin resistance by creating null mice models. Here, for each Aim, I will discuss the progresses made during the K99 phase of the award and describe the future experiments as the original plans have been updated in light ofthe current results.