The Role of Inflammation in Cardiovascular Disease

炎症在心血管疾病中的作用

• 批准号: 9978598
• 负责人: David G Harrison
• 金额: $ 241.31万
• 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/9978598
• 关键词: Adaptive Immune System; Address; Angiotensin II; Antigen Presentation; Atherosclerosis; Biological Assay; Biology; Blood Pressure; Blood Vessels; CD28 gene; Cardiovascular Diseases; Catecholamines; Cause of Death; Cell physiology; Cells; Cities; Collaborations; Coronary Arteriosclerosis; Dendritic Cells; Dimerization; Disease; Epigenetic Process; Event; Excess Dietary Salt; Genetic Transcription; Goals; Human; Hybridomas; Hyperlipidemia; Hypertension; Immune; Immunity; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-6; Laboratories; Lead; Lesion; Maintenance; Major Histocompatibility Complex; Matrix Metalloproteinases; Measurement; Mediating; Memory; Molecular; Morbidity - disease rate; Mus; Myelogenous; Myeloid-derived suppressor cells; Neuraxis; Nuclear Translocation; Oxidation-Reduction; Oxidative Stress; Pathology; Pathway interactions; Patients; Peptides; Peptidyl-Dipeptidase A; Phenotype; Post-Translational Protein Processing; Process; Production; Program Research Project Grants; Proteins; Proteome; Proteomics; Public Health; Pyruvate Kinase; Reactive Oxygen Species; Renal function; Research; Resolution; Risk Factors; Role; Signal Transduction; Societies; Sodium; Stimulus; Suppressor-Effector T-Lymphocytes; Sympathetic Nervous System; T cell response; T memory cell; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Text; Ursidae Family; Warburg Effect; adduct; cancer cell; cytokine; disability; disabling disease; immunogenic; immunogenicity; kidney dysfunction; macrophage; mortality; mouse model; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; programs; screening; small molecule

PROJECT SUMMARY The overall goal of this Program Project Grant is to understand how immune cells including macrophages, dendritic cells (DCs) and T cells are activated and contribute to cardiovascular diseases including atherosclerosis and hypertension. The major theme is that common insults including atherogenic risk factors, catecholamines, oxidative stress, angiotensin II and excessive salt lead to disregulation of immune cells, leading to local and systemic inflammation. These events promote vascular lesion formation, renal dysfunction, blood pressure elevation and likely other inflammatory processes, common to humans with cardiovascular disease. Project 1 will examine how T cells are activated in hypertension, particularly the role of signals from the central nervous system. Novel mice will be used that allow study of how the sympathetic nervous system stimulates dendritic cells and ultimately T cells. Drs. Harrison and Bernstein have identified an oxidative protein modification that promotes DC immunogenicity. An important collaboration will be to identify specific isoketal adducted peptides in MHC1 that are capable of activating T cells responsible for hypertension. Studies will also address how memory cells participate in hypertension caused by repeated hypertensive stimuli. Studies with Project 3 will examine Studies performed with project 2 will examine epigenetic alterations of T cell subtypes in humans with hypertension. Dr. Cornelia Weyand, the director of project 2 has discovered that macrophages from patients with coronary artery disease or hypertension have a hyperinflammatory phenotype and produce excess IL-1β and IL-6. Together with Core A and Dr. Harrison, Dr. Weyand has shown that reactive oxygen species induce dimerization of PKM2 and its nuclear translocation, where it promotes cytokine production and feed-forward activation of glycolytic flux; a pathology resembling the Warburg effect of cancer cells. This project will define factors that modulate the oligomeric state of PKM2, determine how it leads to cytokine transcription, and examine its role in both atherosclerosis and hypertension. As part of project 2, Dr. Weyand will seek to examine the efficacy of several promising small molecules to normalize function of macrophages from humans with atherosclerosis and hypertension. Dr. Bernstein, the director of project 3, brings to bear his expertise in the biology of the angiotensin I-converting enzyme (ACE). His group will define previously unrecognized roles of ACE in the initiation, maintenance and resolution of inflammation, by modifying cytokine production, antigen presentation in MHC-1 and function of myeloid suppressor cells. Through collaboration with Dr. Markus Kalkum at the City of Hope, Dr. Bernstein will examine how ACE influences the macrophage proteome and peptidome. All projects make use of Core A, which provides expertise in measurement of reactive oxygen species. Overall, this program project grant promises to provide new understanding of the molecular mechanisms of inflammation in cardiovascular diseases and promises to identify new therapeutic targets to reduce morbidity and mortality in these common and devastating illnesses.

项目摘要 这项计划项目资助的总体目标是了解包括巨噬细胞在内的免疫细胞， 树突状细胞（DC）和T细胞被激活并导致心血管疾病， 动脉粥样硬化和高血压。主要的主题是，常见的损伤，包括动脉粥样硬化的危险因素， 儿茶酚胺、氧化应激、血管紧张素II和过量的盐导致免疫细胞失调， 导致局部和全身炎症。这些事件促进血管病变形成、肾功能障碍， 血压升高和可能的其他炎症过程，常见于心血管疾病患者 疾病项目1将研究T细胞在高血压中是如何被激活的，特别是来自高血压的信号的作用。 中枢神经系统新的小鼠将被用来研究交感神经系统如何 刺激树突细胞并最终刺激T细胞。哈里森和伯恩斯坦博士发现了一种氧化蛋白 促进DC免疫原性的修饰。一个重要的合作将是确定具体的异缩酮 MHC 1中的加合肽能够激活导致高血压的T细胞。研究还将 解决记忆细胞如何参与重复高血压刺激引起的高血压。外贸 项目3将检查与项目2一起进行的研究将检查T细胞亚型的表观遗传改变， 高血压患者。科尔内利亚·韦安德博士，项目2的负责人发现巨噬细胞 来自冠状动脉疾病或高血压患者的具有高度炎症表型并产生 过量的IL-1β和IL-6。韦安德博士与核心A和哈里森博士一起证明，活性氧 物种诱导PKM 2的二聚化及其核转位，在那里它促进细胞因子的产生， 糖酵解通量的前馈激活;类似于癌细胞的瓦尔堡效应的病理学。这 该项目将定义调节PKM 2寡聚状态的因素，确定它如何导致细胞因子 转录，并研究其在动脉粥样硬化和高血压中的作用。作为项目2的一部分，韦安德博士 将寻求检查几种有希望的小分子使巨噬细胞功能正常化的功效 动脉粥样硬化和高血压患者的血液样本。项目3的主任伯恩斯坦博士提出了他的观点 血管紧张素I转换酶（ACE）生物学专业知识。他的团队将在之前定义 ACE通过修饰细胞因子在炎症的发生、维持和消退中的未被认识的作用 MHC-1的产生、抗原呈递和髓系抑制细胞的功能。通过协作 伯恩斯坦博士将与希望之城的马库斯·卡尔库姆博士一起研究ACE如何影响巨噬细胞 蛋白质组和肽组。所有项目都利用核心A，它提供衡量 活性氧物质。总的来说，这项计划项目赠款承诺提供新的理解， 心血管疾病炎症的分子机制，并有望确定新的治疗方法 目标是降低这些常见和毁灭性疾病的发病率和死亡率。

项目成果

Editorial: Vascular Inflammation in Systemic Autoimmunity.

社论：全身性自身免疫性血管炎症。

• DOI: 10.3389/fimmu.2016.00471
• 发表时间: 2016
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Ramirez,GiuseppeA;Weyand,Cornelia;Vaglio,Augusto;Manfredi,AngeloA
• 通讯作者: Manfredi,AngeloA