Amelioration of Insulin Resistance by Inhibiting Non-Canonical Insulin Signaling

 描述(由申请人提供)：我们实验室研究的首要目标是更好地了解2型糖尿病的发病机制，并开发治疗方法来改善这些结果。我们的NIH K01资助了关于脂肪组织中驱动胰岛素抵抗的机制的研究，利用无偏见的定量蛋白质组学来确定新的途径。这一方法的最大成功之一是发现ERK激酶的激活，通过PPARγ的失调导致脂肪组织的转录变化。虽然在肿瘤学和信号转导的背景下对ERK的生物学了解很多，但对于ERK在肥胖、胰岛素抵抗和糖尿病发病机制中的作用却知之甚少。事实上，能够完全阻断ERK激活的MEK抑制剂最近已经被FDA批准。这些化合物在患者和小鼠模型中都有效，可以延缓某些癌症的生长。我们的初步数据表明，用MEK抑制剂治疗肥胖、胰岛素抵抗的小鼠，部分是通过改善PPARγ靶基因的转录激活来改善全身葡萄糖稳态。在这项提案中，我们的目标是确定产生这些有益影响的机制。在具体目标1中，我们将研究γ/ERK抑制剂对PPAR的依赖和非依赖作用。在特定的目标2中，我们将研究MEK/ERK的转录和蛋白质组学结果，以确定ERK在体内的作用靶点。这些数据将以K01奖的发现为基础，在确定的获奖期内完成，并可能有助于开发可迅速转化为临床研究的2型糖尿病的新疗法。

 DESCRIPTION (provided by applicant): The overarching goal of our laboratory's research is to better understand the pathogenesis of type 2 diabetes and develop therapeutic manipulations to improve these outcomes. Our NIH K01 funded research into mechanisms driving insulin resistance in adipose tissue utilized unbiased quantitative proteomics to identify novel pathways. One of the top hits from this approach identified activation of ERK Kinase leading to transcriptional alterations in adipose tissue via dysregulation of PPARγ. Although much is known about the biology of ERK in the context of oncology and signal transduction, much less is known about the role in the pathogenesis of obesity, insulin resistance and diabetes. Indeed, MEK inhibitors capable of completely blocking ERK activation have recently been approved by the FDA. These compounds effective in both patients and mouse models at delaying the growth of certain cancers. Our preliminary data demonstrate that treating obese, insulin resistant mice with MEK inhibitors improves whole body glucose homeostasis in part through improvements in transcriptional activation of PPAR γ target genes. In this proposal we aim to identify the mechanisms responsible for these beneficial effects. In specific aim 1 we will examine the PPARγ-dependent and -independent effects of MEK/ERK inhibitors. In specific aim 2 we will examine the transcriptional and proteomic consequences of MEK/ERK to identify targets of ERK action in vivo. These data would build upon the findings from the K01 award, be completed in a defined award period, and potentially contribute toward novel treatments for type 2 diabetes that could be rapidly translated to clinical investigation.