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：
8872494
负责人：
ALEXANDER BANKS
金额：
$ 7.99万
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/8872494
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 Diet Energy Metabolism Euglycemic Clamping FDA approved Fatty acid glycerol esters Funding Gene Expression Gene Targeting Glucose Glucose Clamp Goals Growth Hormones In Vitro Insulin Insulin Resistance Investigation Knock-in Mouse Knowledge Laboratory Research Lead Liver MAP Kinase Gene MEKs Malignant Neoplasms Measures Mentored Research Scientist Development Award Metabolic Morbidity - disease rate Mus Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Outcome 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 human MAP3K1 protein improved in vivo inhibitor/antagonist insight insulin sensitivity insulin signaling insulin tolerance mortality mouse model novel oncology public health relevance 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（由适用提供）：我们实验室研究的总体目标是更好地了解2型糖尿病的发病机理并开发治疗性操作以改善这些结果。我们的NIH K01资助了促进脂肪组织中胰岛素抵抗的机制的研究，利用了无偏定量蛋白质组学来鉴定新途径。这种方法中的最高命中之一确定了ERK激酶的激活，导致通过PPARγ失调而导致脂肪组织中的转录改变。尽管在肿瘤学和信号转导的背景下，ERK的生物学知之甚少，但对肥胖，胰岛素抵抗和糖尿病的发病的作用知之甚少。实际上，FDA最近批准了能够完全阻断ERK激活的MEK抑制剂。这些化合物在患者和小鼠模型中有效，以延迟某些癌症的生长。我们的初步数据表明，用MEK抑制剂治疗肥胖的胰岛素耐药小鼠可以通过改善PPARγ靶基因的转录激活来改善全身葡萄糖稳态。在此提案中，我们旨在确定负责这些有益作用的机制。在特定目标1中，我们将检查MEK/ERK抑制剂的PPARγ依赖性和非依赖性作用。在特定目标2中，我们将检查MEK/ERK的转录和蛋白质组学后果，以识别体内ERK作用的靶标。这些数据将基于K01奖项的发现，在定义的奖励期内完成，并有可能为2型糖尿病的新型治疗做出贡献，这些糖尿病可以迅速转化为临床研究。