Inflammatory and stress signaling networks in metabolic disease

代谢疾病中的炎症和应激信号网络

基本信息

批准号：
9062429
负责人：
GOKHAN S HOTAMISLIGIL
金额：
$ 44.41万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-03-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9062429
关键词：
Adult Affect Asthma Atherosclerosis Biological Assay Cardiovascular Diseases Cells Cellular Stress Chronic Complex Data Development Diabetes Mellitus Double-Stranded RNA Epidemic Event Goals Health Immune Immune response Inflammation Inflammatory Insulin Insulin Resistance Laboratories Lead Ligands Link Lipids MAPK8 gene Malignant Neoplasms Mediating Mediator of activation protein Metabolic Metabolic Diseases Metabolic stress Metabolic syndrome Metabolism MicroRNAs Mission Molecular NCOA6 gene Nutrient Obesity Overweight Pathogenesis Pathology Pathway interactions Phosphorylation Phosphotransferases Play Population Process Proteins RNA RNA Binding Regulation Research Risk Role Signal Pathway Signal Transduction Signaling Molecule Small Nucleolar RNA Stress System Testing Translating Translations United States National Institutes of Health Work base eIF-2 Kinase fight against in vivo insight new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics pathogen research study response treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The close integration of immune and metabolic responses associated with obesity lead to the development of metabolic diseases such as insulin resistance, diabetes, and atherosclerosis. However, the endogenous molecules that signal metabolic stress and the mechanisms that sense and relay such signals to metabolic and immune response systems are incompletely understood. The double stranded RNA-activated protein kinase PKR is activated in response to pathogens and nutrients, and work by our laboratory and others suggests that PKR plays an important role in integrating signaling networks that modulate inflammation and the development of insulin resistance. Based on our preliminary data we propose that the study of PKR activation represents an opportunity to identify the metabolic signals and novel mechanisms at play in immunometabolic regulation. Therefore, the objective of this proposal is to characterize the endogenous lipids and RNAs that modulate PKR activity and the formation of the active PRK complex in the setting of metabolic stress, with the goal of translating these findings to a broader understanding of the molecular signals that contribute to the integration of metabolic stresses and inflammation in obesity. We believe that successful completion of this work has the potential to highlight new therapeutic targets and strategies for use in the fight against the epidemic of obesity and related pathologies.

描述（由申请人提供）：与肥胖相关的免疫和代谢反应的紧密整合导致代谢疾病的发展，例如胰岛素抵抗，糖尿病和动脉粥样硬化。然而，未完全理解了这些信号和代谢反应系统的内源分子以及将这些信号传递到代谢和免疫反应系统的机制。双链RNA激活的蛋白激酶PKR被激活，以响应病原体和营养素，我们的实验室和其他工作表明，PKR在整合调节炎症和胰岛素抵抗发展的信号网络中起着重要作用。根据我们的初步数据，我们建议对PKR激活的研究代表了一个机会，可以识别免疫代谢调节中的代谢信号和新型机制。因此，该提案的目的是表征内源性脂质和RNA在代谢应激的情况下调节PKR活性以及主动PRK复合物的形成，目的是将这些发现转化为对分子信号的更广泛的理解，从而有助于对OBESTEN中代谢应力和炎症的整合。我们认为，这项工作的成功完成有可能着重介绍与肥胖症和相关病理流行的战斗中使用新的治疗靶标和策略。