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: 9171375
• 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/9171375
• 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; Complement; 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; Immunologics; Individual; Inflammasome; Inflammation; Inflammatory; Insulin; Insulin Resistance; Lesion; Link; Lipids; Lipoproteins; MAPK8 gene; Macrophage Activation; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Nutrient; Obesity; Pathogenesis; Pathologic; 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; cardiovascular risk factor; cell type; diabetic; eIF-2 Kinase; experimental study; 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; public health relevance; 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的心血管疾病（CVD）是美国发病率和死亡率的主要原因。动脉粥样硬化的特征是脂质在动脉壁中的积累，这是一种炎症性疾病，其中几种包括巨噬细胞在内的免疫效应子起着核心作用。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，但是将无序代谢与炎症联系起来的机制以及动脉粥样硬化的发展仍然有待阐明。我们发表的工作和初步数据表明，在肥胖症的背景下，双链RNA激活的蛋白激酶PKR被激活，在肥胖症的背景下，它在驱动炎症和葡萄糖稳态恶化中起着批评作用。在巨噬细胞中，暴露于脂肪毒性信号和脂蛋白激活PKR。此外，PKR是NLRP3炎症体激活的关键成分，以及JNK等应力信号通路，这与糖尿病和动脉粥样硬化的发病机理有关。此外，在该提案中提供的支持数据中，我们证明了对PKR缺陷小鼠的动脉粥样硬化斑块发育的重要保护。基于这些发现，我们的总体假设是，通过调节炎症活性，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在巨噬细胞的激活和功能中的作用，以及评估PKR在体内发展动脉粥样硬化中的整个身体和巨噬细胞特异性的要求来检验假设。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。这项工作的创新在于通过确定血脂异常与免疫细胞炎症激活之间的机械联系来研究一种新型的动脉粥样硬化治疗方法。