The role of immunometabolic pathways in atherosclerosis

免疫代谢途径在动脉粥样硬化中的作用

• 批准号: 8967582
• 负责人: GOKHAN S HOTAMISLIGIL
• 金额: $ 40.38万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-15 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967582
• 关键词: Arterial Fatty Streak; Arteries; Atherosclerosis; Automobile Driving; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; Cardiovascular Diseases; Cause of Death; Cell physiology; Cells; Cellular Stress; Cessation of life; Chronic; Coronary; Data; Deterioration; Development; Diabetes Mellitus; Disease; Double-Stranded RNA; Dyslipidemias; Exposure to; Glucose; Goals; Health; High Fat Diet; Histology; Human; Immune; Immune Cell Activation; Individual; Inflammation; Inflammatory; Insulin; Insulin Resistance; Link; Lipids; Lipoproteins; MAPK8 gene; Macrophage Activation; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Nutrient; Obesity; Pathogenesis; Pathway interactions; Peripheral arterial disease; Phenotype; Play; Protein Biosynthesis; Public Health; Publishing; Reporting; Research; Risk; Risk Factors; Role; Saturated Fatty Acids; Signal Pathway; Signal Transduction; Stimulus; Stress; System; Testing; Therapeutic; Tissues; United States National Institutes of Health; Work; atherogenesis; base; biological adaptation to stress; blood glucose regulation; cell type; diabetic; eIF-2 Kinase; in vivo; innovation; insight; lipid metabolism; liver function; loss of function; macrophage; molecular targeted therapies; mortality; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pathogen; plaque lesion; research study; response

DESCRIPTION (provided by applicant): Atherosclerosis and associated cardiovascular disease (CVD) are the leading cause of morbidity and mortality in the US. Atherosclerosis is characterized by the accumulation of lipids in the artery wall, and is an inflammatory disease in which several immune effectors including macrophages play a central role. Obesity, insulin resistance, diabetes, and dyslipidemia are all major risk factors for CVD, but the mechanisms that link disordered metabolism to inflammation and the development of atherosclerosis remain to be elucidated. Our published work and preliminary data demonstrate that the double stranded RNA activated protein kinase, PKR, is activated in the context of obesity, where it plays a critica role in driving inflammation and the deterioration of glucose homeostasis. In macrophages, exposure to lipotoxic signals and lipoproteins activate PKR. In addition, PKR is a critical component for the activation of the NLRP3 inflammasome, and stress signaling pathways such as JNK, which are implicated in the pathogenesis of both diabetes and atherosclerosis. In addition, in supporting data presented in this proposal we demonstrate a significant protection against atherosclerotic plaque development in PKR-deficient mice. Based on these findings our overarching hypothesis is that by modulating inflammatory activity, insulin action, and protein synthesis, PKR links cellular stress and metabolic signals to chronic inflammation and atherosclerosis. The experiments described in this proposal will test that hypothesis by determining the role of PKR in the activation and function of macrophages, and by assessing the whole body and macrophage-specific requirement for PKR in the development of atherosclerosis in vivo. This contribution will expand our understanding of the link between nutrient stress and the development of cardiometabolic disease. The innovation of this work lies in investigating a novel approach to atherosclerosis therapy by identifying the mechanistic link between dyslipidemia and inflammatory activation of immune cells.

描述（由申请人提供）：动脉粥样硬化和相关心血管疾病（CVD）是美国发病和死亡的主要原因。动脉粥样硬化的特征是动脉壁中脂质积聚，是一种炎症性疾病，其中包括巨噬细胞在内的多种免疫效应物发挥核心作用。肥胖、胰岛素抵抗、糖尿病和血脂异常都是CVD的主要危险因素，但代谢紊乱与炎症和动脉粥样硬化发展之间的联系机制仍有待阐明。我们发表的工作和初步数据表明，双链 RNA 激活蛋白激酶 PKR 在肥胖背景下被激活，在驱动炎症和葡萄糖稳态恶化方面发挥着关键作用。在巨噬细胞中，暴露于脂毒性信号和脂蛋白会激活 PKR。此外，PKR 是激活 NLRP3 炎性体和 JNK 等应激信号通路的关键组成部分，这些通路与糖尿病和动脉粥样硬化的发病机制有关。此外，在支持本提案中提出的数据中，我们证明了对 PKR 缺陷小鼠中动脉粥样硬化斑块发展的显着保护作用。基于这些发现，我们的总体假设是，通过调节炎症活动、胰岛素作用和蛋白质合成，PKR 将细胞应激和代谢信号与慢性炎症和动脉粥样硬化联系起来。本提案中描述的实验将通过确定 PKR 在巨噬细胞激活和功能中的作用，并通过评估全身和巨噬细胞在体内动脉粥样硬化发展中对 PKR 的特异性需求来检验该假设。这一贡献将扩大我们对营养应激与心脏代谢疾病发展之间联系的理解。这项工作的创新之处在于通过确定血脂异常和免疫细胞炎症激活之间的机制联系来研究动脉粥样硬化治疗的新方法。