THE ROLE OF ACE IN INFLAMMATION AND HYPERTENSION

ACE 在炎症和高血压中的作用

• 批准号: 9978627
• 负责人: KENNETH E BERNSTEIN
• 金额: $ 69.91万
• 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/9978627
• 关键词: Address; Affect; Angiotensin II; Anti-Inflammatory Agents; Antigen-Presenting Cells; Antigens; Biochemistry; Biological; Blocking Antibodies; Blood Pressure; CD8-Positive T-Lymphocytes; Cardiovascular Diseases; Catalytic Domain; Cells; Complex; Data; Dendritic Cells; Development; Effectiveness; Epitopes; Hand; Hybridomas; Hypertension; Immune; Immune response; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interleukin-12; Intervention; Ligands; MHC Class I Genes; Measures; Modeling; Monoclonal Antibodies; N Domain; Natural Immunity; Pathologic; Pathology; Peptide Hydrolases; Peptides; Peptidyl-Dipeptidase A; Phase; Play; Process; Production; Proteins; Publishing; Reagent; Role; Series; Signal Transduction; Source; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TNF gene; Techniques; Testing; Work; adduct; cytokine; immune activation; immunogenic; immunoreaction; inhibitor/antagonist; insight; macrophage; monocyte; neoantigens; novel; novel therapeutic intervention; response; sensor; tool

PROJECT SUMMARY A tremendous amount of published data indicates that cellular inflammation plays a critical role in the development of hypertension. In a sense, any immune challenge initiates a series of responses that are similar regardless of the initiating agent. In other words, whether challenged by the development hypertension or by infection, the initial reaction of the immune system is innate immunity. Here, monocytes, macrophages and other cells detect an initial insult and react by elaborating pro-inflammatory cytokines (TNFα, IL-12 etc) that amplify the initial response. Specific Aim 1 examines the role of angiotensin converting enzyme (ACE) in macrophage expression of cytokines during the initial (innate) immune response to hypertension. Here the focus is how the N-domain of ACE affects macrophage differentiation and the expression of pro- and anti- inflammatory cytokines. The innate response is followed by the adaptive phase of the immune response centered on the interaction of T cells with dendritic cells and other antigen presenting cells (APCs). APCs present antigenic peptides in the context of MHC molecules and evoke a variety of T cell responses. ACE is a peptidase and Specific Aim 2 is to study the role of ACE in APC activation and peptide presentation during hypertension. Ultimately, the T cells that induce pathology in hypertension are activated by specific peptide ligands that engage the T cell receptor. This is well known, but it has critical relevance to hypertension. While studies have suggested that a class of T cells called CD8+ T cells is critical to the development of hypertension, we know essentially nothing about the epitopes that become immunogenic in hypertension or about the precise CD8+ T cells that respond to these epitopes. Specific Aim 3 will address this by using the technique of T cell hybridomas to clone and study the precise T cell receptors that interact with hypertensive epitopes. This will provide a powerful new tool to study where and when immune epitopes are made during the development of hypertension. This tool will also be used to clone (and thus identify) the precise proteins that are the source of the hypertensive epitopes. These aims will greatly enhance our understanding of how the inflammatory response contributes to hypertension, and they will also provide new targets for intervention.

项目摘要 大量已发表的数据表明，细胞炎症在炎症反应中起着关键作用。 发生高血压。从某种意义上说，任何免疫挑战都会引发一系列反应， 类似的，不管起始剂。换句话说，无论是挑战发展高血压， 或感染，免疫系统的最初反应是先天免疫。这里单核细胞巨噬细胞 其他细胞检测到初始损伤并通过产生促炎细胞因子（TNFα、IL-12等）作出反应 放大了最初的反应具体目标1检查血管紧张素转换酶（ACE）在 巨噬细胞表达的细胞因子在初始（先天）免疫反应高血压。这里 重点是ACE的N-结构域如何影响巨噬细胞分化以及促分化因子和抗分化因子的表达。 炎性细胞因子先天反应之后是免疫反应的适应性阶段 其中心是T细胞与树突状细胞和其他抗原呈递细胞（APC）的相互作用。APCs 在MHC分子的背景下呈递抗原肽并引起多种T细胞应答。ACE是一个 肽酶和特异性目的2是研究ACE在APC激活和肽呈递中的作用， 高血压最终，诱导高血压病理的T细胞被特定肽激活 与T细胞受体结合的配体。这是众所周知的，但它与高血压密切相关。而 研究表明，一类称为CD 8 + T细胞的T细胞对肿瘤的发展至关重要。 高血压，我们基本上对高血压中成为免疫原性的表位一无所知， 对这些表位做出反应的CD 8 + T细胞。具体目标3将通过使用 T细胞杂交瘤技术克隆和研究与高血压相互作用的精确T细胞受体 表位这将提供一个强大的新工具，研究免疫表位在哪里和何时产生， 高血压的发展。该工具还将用于克隆（从而识别）精确的蛋白质 高血压表位的来源。这些目标将大大提高我们对如何 炎症反应是导致高血压的原因之一，也将为干预提供新的靶点。