The Role of The T Cell In The Genesis of Hypertension

T 细胞在高血压发生中的作用

• 批准号: 9273740
• 负责人: David G Harrison
• 金额: $ 39.25万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-08 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9273740
• 关键词: Adoptive Transfer; Adult; Affect; Angiotensin II; Animals; Appearance; Blood Pressure; Blood Vessels; Bone Marrow Transplantation; Brain; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; DOCA; Data; Dendritic Cells; Dendritic cell activation; Denervation; Disease; Diuretics; Employee Strikes; Etiology; Exposure to; Funding; Health; Heart failure; Hypertension; Immunity; Inflammation; Inflammatory Response; Interferons; Intervention; Kidney; Laboratories; Lead; Link; Lymphoid; Memory; Modeling; Mus; Myocardial Infarction; NADPH Oxidase; Natural Immunity; Nerve; Neuraxis; Organ; Pathway interactions; Play; Population; Positioning Attribute; Production; Reactive Oxygen Species; Renal function; Research; Research Proposals; Risk Factors; Role; Signal Transduction; Sodium; Sodium Chloride; Spleen; Stimulus; Stroke; Subfornical Organ; Superoxides; Sympathetic Nervous System; T memory cell; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Vascular remodeling; adaptive immunity; base; blood pressure regulation; common treatment; cytokine; experience; insight; macrophage; novel strategies; novel therapeutics; prevent; recombinase-mediated cassette exchange; response; salt sensitive hypertension; saluretic; tool; vasoconstriction

DESCRIPTION (provided by applicant): In the past several 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 T cells, macrophages and dendritic cells, which in turn affect the vasculature and kidney to raise blood pressure. Studies in the past funding cycle indicate that actions of angiotensin II on circumventricular organs (CVOs) and in particular the subfornical organ (SFO) activate T cells and entry of these cells into the kidney and vasculature, where they promote vascular remodeling, vasoconstriction, salt and volume retention and ultimately blood pressure elevation. We have recently found that CD8+ T cells have a predominant role in the initial (first 2 week) response to angiotensin II and DOCA-salt challenge, and that mice lacking these cells display blunted hypertensive responses to angiotensin II and do not retain sodium and volume in response to angiotensin II. We propose that sympathetic stimuli, acting either on the kidney or secondary lymphoid organs activate dendritic cells (DCs), in part by stimulating DCs to produce reactive oxygen species (ROS) production. By deleting p22phox in the SFO using cre-lox technology, we will prevent the central actions of angiotensin II, and will conversely enhance the central actions of ang II by deleting SOD3 in the SFO. These interventions will determine if the actions of ang II on the SFO are critical for DC and renal CD8+ T cell activation. We will also examine if DC activation occurs predominantly in the spleen or in the kidney by performing selective renal denervation. Preliminary data indicate that angiotensin II increases DC superoxide production by 6 fold, largely via the Nox2 based NADPH oxidase. In aim 2, we will determine if central actions of angiotensin II promote DC ROS production and to perform studies to determine how this promotes CD8+ T cell activation. Bone marrow transplant of Nox2-/- cells will provide information regarding the role of DC Nox2 in hypertension. Finally, we will examine the role of memory CD8+ T cells in responses to repeated challenges with angiotensin II. These studies will focus on the roles of interactions between CD27 and CD70 and the roles of signals derived from CD4+ cells in CD8+ memory cell formation. Overall, these studies promise to further our understanding of hypertension and provide new therapeutic options for this common and difficult to treat disease.

描述（申请人提供）：在过去的几年中，我们实验室和其他实验室的研究表明，先天免疫和适应性免疫在高血压的发生中发挥着关键作用。该项目的主要假设是中枢神经系统协调 T 细胞、巨噬细胞和树突状细胞的活动，进而影响脉管系统和肾脏，从而升高血压。过去资助周期的研究表明，血管紧张素 II 对心室周围器官 (CVO)、特别是穹窿下器官 (SFO) 的作用会激活 T 细胞，并使这些细胞进入肾脏和脉管系统，促进血管重塑、血管收缩、盐和容量潴留，并最终导致血压升高。我们最近发现 CD8+ T 细胞在血管紧张素 II 和 DOCA 盐挑战的初始（前两周）反应中起主导作用，缺乏这些细胞的小鼠对血管紧张素 II 的高血压反应减弱，并且不会保留钠和体积以响应血管紧张素 II。我们提出，作用于肾脏或次级淋巴器官的交感神经刺激可部分通过刺激树突状细胞（DC）产生活性氧（ROS）来激活树突状细胞（DC）。通过使用cre-lox技术删除SFO中的p22phox，我们将阻止血管紧张素II的中枢作用，并且反过来通过删除SFO中的SOD3来增强ang II的中枢作用。这些干预措施将确定 ang II 对 SFO 的作用是否对 DC 和肾 CD8+ T 细胞激活至关重要。我们还将通过选择性肾去神经术来检查 DC 激活是否主要发生在脾脏或肾脏中。初步数据表明，血管紧张素 II 使 DC 超氧化物的产生增加了 6 倍，这主要是通过基于 Nox2 的 NADPH 氧化酶实现的。在目标 2 中，我们将确定血管紧张素 II 的中枢作用是否促进 DC ROS 产生，并进行研究以确定这如何促进 CD8+ T 细胞激活。 Nox2-/- 细胞的骨髓移植将提供有关 DC Nox2 在高血压中的作用的信息。最后，我们将研究记忆 CD8+ T 细胞在应对血管紧张素 II 反复挑战中的作用。这些研究将重点关注 CD27 和 CD70 之间相互作用的作用以及 CD4+ 细胞衍生的信号在 CD8+ 记忆细胞形成中的作用。总的来说，这些研究有望进一步加深我们对高血压的了解，并为这种常见且难以治疗的疾病提供新的治疗选择。