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

基本信息

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
项目类别：
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

项目摘要

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.

先天性和适应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。巨噬细胞，通过多种效应功能导致炎症损伤，例如炎症细胞因子释放、脂质和碎片去除效率低下、基质降解和抗原在初步研究中，我们已经表明来自患者的巨噬细胞。冠状动脉疾病或高血压具有高炎症表型并产生过量的 IL-1 和 IL-6 患者来源的巨噬细胞中细胞因子的过量产生可通过限制葡萄糖或我们已经确定了清除活性氧（ROS）的潜在分子机制。丙酮酸激酶 M2 (PKM2) 是一种氧化还原敏感分子，作为四聚体可充当细胞质代谢激酶并作为二聚体充当促进炎症的核蛋白激酶。在患有动脉粥样硬化或高血压疾病的患者中，PKM2 主要二聚化并导入到细胞核，一种将代谢调节改变与过度炎症免疫联系起来的异常现象。本质上，在心血管疾病患者中，葡萄糖过度利用会刺激炎症巨噬细胞通过 ROS 诱导的 PKM2 核转位发挥作用，其中该酶促进细胞因子的产生糖酵解的产生和前馈激活；重新组装癌细胞的瓦尔堡效应的病理学。项目 2 将与项目 1 和 3 密切合作，定义耦合的基本分子机制。血管炎症的代谢和功能异常旨在发现可操作的方法。炎症免疫反应的诊断和治疗靶点，我们将重点关注葡萄糖-ROS- PKM2 途径。具体目标 1 将寻求从机制上了解 ROS 的产生和糖酵解的过程。通量决定 PKM2 的寡聚状态、细胞定位和功能具体目标 2 致力于冠状动脉疾病和高血压中巨噬细胞的比较代谢和功能分析剖析共享和选择性的病理学，以了解患者来源的巨噬细胞是如何产生的。通过代谢重新编程，这一目标将利用一种新的表观遗传技术（ATAC seq）来识别在特定目标 3 中，我们将揭示 PKM2 在调节致病性巨噬细胞功能谱并确定葡萄糖成瘾对 T 细胞的影响免疫（Th1、Th17、Treg 和 Thf 免疫反应）。具体目标 4 将探讨分子是否存在免疫反应。炎症巨噬细胞和癌细胞之间的共性可用于新疗法在临床前研究中，我们将测试是否开发出小分子抑制剂来治疗心血管疾病。癌细胞中的瓦尔堡效应可以重新用于抑制心血管疾病中的炎症。