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.

项目总结

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