THE ROLE OF ACE IN INFLAMMATION AND HYPERTENSION

项目总结 大量已发表的数据表明，细胞炎症在 高血压的发展。在某种意义上，任何免疫挑战都会引发一系列反应，这些反应是 无论引发剂是什么，都是相似的。也就是说，无论是受到高血压发展的挑战， 或者通过感染，免疫系统的初始反应是先天免疫。在这里，单核细胞，巨噬细胞 而其他细胞检测到最初的伤害，并通过阐述促炎细胞因子(肿瘤坏死因子α，IL-12等)做出反应。 这放大了最初的反应。特定目的1研究血管紧张素转换酶(ACE)在 高血压初始(先天)免疫反应中巨噬细胞细胞因子的表达。在这里， 焦点是血管紧张素转换酶的N区如何影响巨噬细胞的分化和亲抗分子的表达 炎性细胞因子。先天反应之后是免疫反应的适应阶段。 主要集中在T细胞与树突状细胞和其他抗原提呈细胞(APC)的相互作用。APCS 在MHC分子的背景下呈现抗原肽，并激发各种T细胞反应。王牌是一家 目的：研究血管紧张素转换酶在血管紧张素转换酶激活和肽递呈中的作用。 高血压。最终，导致高血压病理的T细胞被特定的多肽激活 与T细胞受体结合的配体。这是众所周知的，但它与高血压有关键的相关性。而当 研究表明，一类名为CD8+T细胞的T细胞对慢性粒细胞白血病的发展至关重要。 高血压，我们基本上对高血压或高血压的免疫原性表位一无所知。 关于对这些表位做出反应的CD8+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。这将为研究免疫表位在何时何地产生提供一个强大的新工具 高血压的发展。这个工具也将被用来克隆(从而识别)精确的蛋白质 它们是高血压表位的来源。这些目标将极大地提高我们对 炎症反应有助于高血压的发生，也将为干预提供新的靶点。

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.