Mechanisms of T cell Activation in Hypertension

高血压中 T 细胞激活的机制

• 批准号: 9978625
• 负责人: David G Harrison
• 金额: $ 57.12万
• 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/9978625
• 关键词: ATAC-seq; Adopted; Adult; Affect; Angiotensin II; Animals; Blood Pressure; Blood Vessels; Bone Marrow; Brain; Cardiovascular Diseases; Cells; Collaborations; Cre-LoxP; Data; Dendritic Cells; Dendritic cell activation; Disease; Epigenetic Process; Etiology; Future; Harvest; Heart failure; Histocompatibility Antigens Class I; Human; Hybridomas; Hypertension; Immune response; Immunity; Inflammation; Inflammatory; Interferon Type II; Interferons; Interleukin-17; Interruption; Intervention; Kidney; Laboratories; Lateral; Lead; Major Histocompatibility Complex; Maps; Mediating; Memory; Methods; Modeling; Molecular; Monitor; Mus; Myocardial Infarction; NADPH Oxidase; Natural Immunity; Neuraxis; Norepinephrine; Organ; Pathway interactions; Peptides; Play; Population; Positioning Attribute; Production; Proteins; Proteomics; Public Health; Reactive Oxygen Species; Renal function; Research; Risk Factors; Role; Signal Transduction; Site; Sodium; Stimulus; Stroke; Subfornical Organ; Superoxides; Sympathetic Nervous System; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Water; adaptive immunity; adduct; cytokine; experimental study; immune activation; immunogenic; in vivo; insight; kidney dysfunction; neoantigens; novel; novel strategies; novel therapeutics; oxidized lipid; peptide I; prehypertension; prevent; receptor; recombinase-mediated cassette exchange; response; salt sensitive hypertension; secondary lymphoid organ; success; terminally differentiated effector memory (TEM) T cells; trafficking; treatment strategy

ABSTRACT In recent years, research from our laboratory and others has shown that innate and adaptive immunity play critical roles in the genesis of hypertension. The major hypothesis of this project is that the central nervous system coordinates actions of dendritic cells (DCs) and T cells, which in turn affect the vasculature and kidney to raise blood pressure. We have also discovered a novel role of isoketal-protein adducts in hypertension. These oxidatively modified proteins accumulate in DCs, lead to DC activation and seem to act as neoantigens. In a recent study, we have also shown that a major site of DC and T cell activation in hypertension is the kidney. These findings are extremely novel, because they show a new role of DCs in hypertension, and we plan to gain further insight into activation of these cells by hypertensive stimuli in vivo. We will interrupt sympathetic outflow by deleting the NADPH oxidase subunit p22phox in the rostroventral lateral medulla using cre-lox technology and will prevent the central actions of angiotensin II by deleting the AT1 receptor (AT1R) in circumventricular organs. We will also examine the direct effect of angiotensin II on DCs by deleting the AT1R in DCs, again using Cre-Lox approaches. The impact of these interventions will be monitored by examining DC isoketal-adduct formation and superoxide production in conjunction with Core A. In aim 2, we will employ novel mice we have made that have soluble forms of class 1 major histocompatibility complexes (MHC1). DCs from these mice shed large quantities of MHC1 and we have adopted methods to harvest isoketal-adducted peptides from these for proteomic analysis. In collaboration with project 3, we will examine the ability of specific isoketal-adducted peptides identified in aim 2 to drive proliferation of hypertension-specific T cell hybridomas. In aim 3, we will examine the role of memory T cells in responses to repeated hypertensive challenges. Our preliminary data show that these have a critical role in modulating salt-sensitive hypertension. A model developed in conjunction with project 3 will be employed. Preliminary data indicate that these repeated challenges promote renal accumulation of effector memory T cells (TEM cells) that produce large amounts of IL- 17A and IFN-. We also find that TEM cells accumulate in the bone marrow of hypertensive mice, and will determine the role of these in responding to repeated hypertensive stimuli, and how the sympathetic nervous system modulates their trafficking and activation. An important aspect of this aim will be to determine if memory T cells of humans with either hypertension or pre-hypertension have epigenetic alterations that predispose to inflammatory cytokine production. These experiments will employ a novel ATAC-seq technology, performed in collaboration with Drs. Weyand and Goronzy in project 2, to map the epigenetic landscape of T cell subsets. Overall, these studies promise to further our understanding of hypertension and provide new therapeutic options for this common and difficult to treat disease.

抽象的 近年来，我们实验室和其他人的研究表明，先天免疫和适应性免疫发挥着作用 在高血压的发生中起关键作用。该项目的主要假设是中枢神经 系统协调树突状细胞 (DC) 和 T 细胞的活动，进而影响脉管系统和肾脏 提高血压。我们还发现异缩酮蛋白加合物在高血压中的新作用。 这些氧化修饰的蛋白质在 DC 中积累，导致 DC 激活，并且似乎充当新抗原。 在最近的一项研究中，我们还表明高血压中 DC 和 T 细胞激活的主要部位是 肾。这些发现非常新颖，因为它们显示了 DC 在高血压中的新作用，我们 计划进一步了解体内高血压刺激对这些细胞的激活。我们会打断 通过删除延髓前腹侧的 NADPH 氧化酶亚基 p22phox 来实现交感神经流出 cre-lox 技术，将通过删除 AT1 受体 (AT1R) 来阻止血管紧张素 II 的中枢作用 室周器官。我们还将通过删除 AT1R 来检查血管紧张素 II 对 DC 的直接影响 在 DC 中，再次使用 Cre-Lox 方法。这些干预措施的影响将通过检查 DC 来监测 与核心 A 一起形成异缩酮加合物和超氧化物。在目标 2 中，我们将采用新颖的 我们制作的小鼠具有可溶形式的 1 类主要组织相容性复合物 (MHC1)。 DC 来自 这些小鼠排出了大量的 MHC1，我们采用了收获异酮缩醛加合物的方法 从这些中提取肽用于蛋白质组分析。与项目3合作，我们将检查具体的能力 目标 2 中鉴定的异缩酮加合肽可驱动高血压特异性 T 细胞杂交瘤的增殖。 在目标 3 中，我们将研究记忆 T 细胞在应对反复高血压挑战中的作用。我们的 初步数据表明，这些在调节盐敏感性高血压方面具有关键作用。一个模型 将采用与项目 3 一起开发的。初步数据表明，这些重复 挑战会促进效应记忆 T 细胞（TEM 细胞）在肾脏的积累，从而产生大量 IL- 17A 和 IFN-。我们还发现 TEM 细胞在高血压小鼠的骨髓中积聚，并且会 确定这些在对反复高血压刺激做出反应中的作用，以及交感神经如何 系统调节它们的运输和激活。这一目标的一个重要方面是确定是否 患有高血压或高血压前期的人的记忆 T 细胞具有表观遗传改变， 易产生炎症细胞因子。这些实验将采用一种新颖的 ATAC-seq 技术， 与博士合作进行。 Weyand 和 Goronzy 参与项目 2，绘制 T 的表观遗传图谱 细胞亚群。总的来说，这些研究有望进一步加深我们对高血压的了解，并提供新的 这种常见且难以治疗的疾病的治疗选择。