The Role of Inflammation in Cardiovascular Disease

项目总结 该计划项目赠款的总体目标是了解包括巨噬细胞在内的免疫细胞如何， 树突状细胞(DC)和T细胞被激活，并与心血管疾病有关，包括 动脉粥样硬化和高血压。主要的主题是常见的侮辱，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和过量的盐会导致免疫细胞的失调， 导致局部和全身炎症。这些事件促进了血管病变的形成，肾功能障碍， 血压升高和可能的其他炎症过程，常见于患有心血管疾病的人类 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 中枢神经系统。将使用新的小鼠来研究交感神经系统如何 刺激树突状细胞，最终刺激T细胞。哈里森博士和伯恩斯坦博士发现了一种氧化蛋白质 提高DC免疫原性的修饰。一项重要的合作将是确定特定的异缩酮 MHC1中能够激活引起高血压的T细胞的加合物多肽。研究还将 阐述记忆细胞如何参与由反复高血压刺激引起的高血压。研究对象： 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学变化 患有高血压的人类。项目2的负责人Cornelia Weyand博士发现巨噬细胞 来自冠状动脉疾病或高血压的患者有高炎性表型并产生 IL-1β和IL-6过多。与核心A和哈里森博士一起，韦恩德博士已经证明了活性氧 物种诱导PKM2二聚化及其核转位，在那里它促进细胞因子的产生和 糖酵解通量的前馈激活；一种类似于癌细胞的沃堡效应的病理。这 该项目将定义调节PKM2寡聚状态的因素，确定它如何导致细胞因子 转录，并检测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，Weyand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有效性 来自患有动脉粥样硬化和高血压的人类。伯恩斯坦博士，项目3的负责人，带来了他的 在血管紧张素转换酶(ACE)生物学方面的专业知识。他的团队将在之前定义 ACE通过改变细胞因子在炎症的启动、维持和消退中的未知作用 髓系抑制细胞的产生、在MHC-1中的抗原提呈和功能。通过协作 伯恩斯坦博士将与马库斯·卡尔库姆博士一起在希望之城研究ACE如何影响巨噬细胞 蛋白质组和多肽组。所有项目都使用Core A，它提供了测量 活性氧物种。总体而言，这项计划项目赠款承诺提供对 心血管疾病炎症的分子机制及其有望找到新的治疗方法 减少这些常见和毁灭性疾病的发病率和死亡率的目标。

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.