Metabolic Regulation of Inflammatory Immune Responses in Cardiovascular Disease

心血管疾病炎症免疫反应的代谢调节

• 批准号: 9978626
• 负责人: Cornelia M. Weyand
• 金额: $ 66.82万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978626
• 关键词: ATAC-seq; Adaptive Immune System; Affect; Antigen Presentation; Antigens; Atherosclerosis; Birds; Blood Vessels; Capillary Electrophoresis; Cardiomyopathies; Cardiovascular Diseases; Cell Nucleus; Cells; Consumption; Coronary Arteriosclerosis; Defect; Diagnostic; Dimerization; Disease; Duct (organ) structure; Endothelial Cells; Enzymes; Epigenetic Process; Equilibrium; Estrogen receptor positive; Ethers; Excision; Failure; Genes; Glucose; Glycolysis; Human; Hypertension; Immune; Immune response; Immune system; Immunity; Immunoassay; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 beta; Interleukin-6; Life; Lipids; Malignant Neoplasms; Metabolic; Molecular; Morbidity - disease rate; Nuclear; Nuclear Protein; Nuclear Translocation; Oxidation-Reduction; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Phagocytosis; Phenotype; Phosphotransferases; Post-Translational Protein Processing; Production; Protein Kinase; Public Health; Pyruvate Kinase; Reactive Oxygen Species; Regulation; Regulatory T-Lymphocyte; Role; STAT3 gene; Shapes; Smooth Muscle Myocytes; System; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissues; United States; Vascular Smooth Muscle; Virulence Factors; Warburg Effect; addiction; aerobic glycolysis; angiogenesis; c-myc Genes; cancer cell; comparative; cytokine; dimer; immunopathology; inflammatory milieu; macrophage; mortality; novel; novel therapeutics; preclinical study; protein kinase R; sensor; small molecule inhibitor; sugar; therapeutic target; transcription factor; vascular inflammation

Abnormalities in the innate and adaptive immune system are key pathogenic factors in cardiovascular disease, including hypertension, atherosclerosis and cardiomyopathy. The current proposal focusses on macrophages, which contribute to inflammatory damage through multiple effector functions, e.g. pro- inflammatory cytokine release, inefficient removal of lipids and debris, matrix degradation and antigen presentation to T lymphocytes. In preliminary studies we have shown that macrophages from patients with coronary artery disease or hypertension have a hyperinflammatory phenotype and produce excess IL-1 and IL-6. Cytokine overproduction in patient-derived macrophages is correctable by restricting glucose or scavenging reactive oxygen species (ROS). We have pinpointed the underlying molecular mechanism to the enzyme pyruvate kinase M2 (PKM2), a redox-sensitive molecule, which as a tetramer functions as a cytoplasmic metabolite kinase and as a dimer acts as an inflammation-promoting nuclear protein kinase. In patients with atherosclerotic or hypertensive disease, PKM2 is primarily dimerized and imported into the nucleus, an abnormality that connects altered metabolic regulation with excess inflammatory immunity. In essence, in patients with cardiovascular disease, glucose overutilization fuels inflammatory macrophage functions through ROS-induced nuclear translocation of PKM2, where the enzyme promotes cytokine production and feed-forward activation of glycolysis; a pathology resembling the Warburg effect of cancer cells. Working closely with Project 1 and 3, Project 2 will define basic molecular mechanisms that couple metabolic and functional abnormalities in vascular inflammation. Aiming for the discovery of actionable diagnostic and therapeutic targets in inflammatory immune responses, we will focus on the glucose-ROS- PKM2 pathway. Specific Aim 1 will seek to mechanistically understand how ROS production and glycolytic flux determine the oligomeric state, cellular localization and function of PKM2. Specific Aim 2 is devoted to a comparative metabolic and functional analysis of macrophages in coronary artery disease and in hypertension to dissect shared and selective pathologies. In an effort to understand how patient-derived macrophages are metabolically reprogrammed, this aim will utilize a novel epigenetic technique (ATAC seq) to identify poised genes and pioneer transcription factors. In Specific Aim 3, we will reveal the role of PKM2 in regulating the spectrum of pathogenic macrophage functions and determine the impact of glucose addiction on T cell immunity (Th1, Th17, Treg and Thf immune responses). Specific Aim 4 will explore whether molecular commonalities between inflammatory macrophages and cancer cells can be exploited for novel therapies in cardiovascular disease. In preclinical studies we will test whether small molecule inhibitors developed to treat the Warburg effect in cancer cells can be repurposed to suppress inflammation in cardiovascular disease.

先天免疫系统和获得性免疫系统的异常是心血管疾病的关键致病因素 疾病，包括高血压、动脉粥样硬化和心肌病。目前的提案重点是 巨噬细胞通过多种效应器功能促进炎症损伤，如促红细胞生成素。 炎性细胞因子的释放、脂类和碎屑的低效清除、基质降解和抗原 呈递给T淋巴细胞。在初步研究中，我们已经表明，来自慢性阻塞性肺疾病患者的巨噬细胞 冠状动脉疾病或高血压具有高炎性表型，并产生过量的IL-1和 IL-6。患者来源的巨噬细胞中细胞因子的过度产生可以通过限制血糖或 清除自由基(ROS)。我们已经确定了潜在的分子机制 丙酮酸激酶M2(PKM2)是一种氧化还原敏感分子，它作为四聚体发挥着 胞浆代谢物激酶和作为二聚体的核蛋白激酶起促进炎症的作用。在……里面 患有动脉粥样硬化或高血压疾病的患者，PKM2主要是二聚体并输入到 核，一种将代谢调节改变与过度炎症免疫联系在一起的异常。在……里面 本质上，在心血管疾病患者中，葡萄糖过度利用助长了炎性巨噬细胞 通过ROS诱导PKM2的核转位发挥作用，其中该酶促进细胞因子 糖酵解的产生和前馈激活；一种类似于癌细胞的沃堡效应的病理。 与项目1和项目3密切合作，项目2将定义耦合的基本分子机制 血管炎症中的代谢和功能异常。旨在发现可操作的 在炎性免疫反应的诊断和治疗靶点上，我们将重点关注葡萄糖-ROS- PKM2途径。具体目标1将试图机械地理解ROS的产生和糖酵解是如何 通量决定了PKM2的低聚状态、细胞定位和功能。具体目标2致力于 冠心病和高血压患者巨噬细胞代谢和功能的比较分析 来剖析共同的和选择性的病理。为了了解患者来源的巨噬细胞是如何 新陈代谢重新编程，这一目标将利用一种新的表观遗传学技术(Atac Seq)来识别镇静。 基因和先锋转录因子。在具体目标3中，我们将揭示PKM2在调节 病理性巨噬细胞功能谱及葡萄糖成瘾对T细胞的影响 免疫(Th1、Th17、Treg和THF免疫反应)。《特定目标4》将探索分子 炎性巨噬细胞和癌细胞之间的共性可被用于新的治疗 心血管疾病。在临床前研究中，我们将测试小分子抑制剂是否被开发用于治疗 癌细胞中的Warburg效应可以被重新利用来抑制心血管疾病中的炎症。