Amelioration of Insulin Resistance by Inhibiting Non-Canonical Insulin Signaling

通过抑制非典型胰岛素信号传导改善胰岛素抵抗

基本信息

批准号：
9000148
负责人：
ALEXANDER BANKS
金额：
$ 8.88万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9000148
关键词：
Acute Adaptor Signaling Protein Adipose tissue Affect Alanine Antidiabetic Drugs Antineoplastic Agents Automobile Driving Award Biochemical Biology CDK5 gene Cardiovascular Diseases Cells Data Death Rate Development Diabetes Mellitus Energy Metabolism Euglycemic Clamping FDA approved Funding Gene Expression Gene Targeting Glucose Glucose Clamp Goals Growth Health High Fat Diet Hormones In Vitro Insulin Insulin Resistance Investigation Knock-in Mouse Knowledge Laboratory Research Lead Liver MAP Kinase Gene MAP3K1 gene MEKs Malignant Neoplasms Measures Mentored Research Scientist Development Award Metabolic Morbidity - disease rate Mus Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity PPAR gamma Pancreas Pathogenesis Pathology Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phosphorylation Phosphorylation Site Phosphotransferases Physiological Population Proteomics Proto-Oncogene Proteins c-akt Ras/Raf Research Role Running Serine Signal Transduction Site Stroke Testing Therapeutic Thiazolidinediones Tissues Transcriptional Activation Translating United States National Institutes of Health Work adiponectin base blood glucose regulation bone clinical investigation diabetic patient feeding glucose metabolism glucose tolerance glucose uptake improved improved outcome in vivo inhibitor/antagonist insight insulin sensitivity insulin signaling insulin tolerance mortality mouse model novel oncology response translational study

项目摘要

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.

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 资助了利用无偏定量蛋白质组学研究脂肪组织中胰岛素抵抗的机制。以确定新的途径，该方法的热门之一确定了 ERK 激酶的激活通过 PPARγ 失调导致脂肪组织的转录改变。人们对 ERK 在肿瘤学和信号转导方面的生物学作用了解甚少，但对于其在肥胖、胰岛素抵抗和糖尿病发病机制中的作用了解甚少。事实上，能够完全阻断 ERK 激活的 MEK 抑制剂最近已获得 FDA 批准。这些化合物在患者和小鼠模型中均能有效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、胰岛素抵抗小鼠可部分通过改善 PPAR 的转录激活来改善全身稳态。在本提案中，我们旨在确定导致这些有益作用的机制。在具体目标 1 中，我们将检查 MEK/ERK 抑制剂的 PPARγ 依赖性和非依赖性作用。 MEK/ERK 的蛋白质组学结果，以确定 ERK 体内作用的靶标。这些数据将建立在 K01 奖项的研究结果的基础上，在规定的奖励期内完成，并可能有助于快速开发 2 型糖尿病的新疗法。转化为临床研究。