The Central Nervous System and T-Cells in Angiotensin II Induced Hypertension

血管紧张素 II 诱发高血压中的中枢神经系统和 T 细胞

• 批准号: 7408839
• 负责人: Paul J Marvar
• 金额: $ 4.68万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-21 至 2009-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7408839
• 关键词: Ablation; Address; Adoptive Transfer; Affect; Aging; Angiotensin II; Angiotensins; Atherosclerosis; B-Lymphocytes; Blood Circulation; Blood Pressure; Blood Vessels; Brain; Brain region; Cells; Chronic; Collaborations; Condition; Data; Diabetes Mellitus; Dissection; Dose; Enzyme Activation; Essential Hypertension; Functional disorder; Generations; Goals; Hypertension; Immunology; Inflammation; Infusion procedures; Kidney; Knowledge; Laboratories; Lead; Mediating; Membrane; Modeling; Mus; NADPH Oxidase; Neuraxis; Organ; Process; Production; Protein Overexpression; Reactive Oxygen Species; Role; Smoking; Sodium; Source; Superoxide Dismutase; Superoxides; T-Cell Activation; T-Lymphocyte; Testing; Third ventricle structure; Vascular Diseases; Vascular Smooth Muscle; Water; Work; cell type; cytokine; human CYBA protein; hypercholesterolemia; neuroregulation; reconstitution; response

DESCRIPTION (provided by applicant): During the past 2 decades, it has become clear that reactive oxygen species (ROS) are important in the genesis of numerous vascular diseases, including atherosclerosis and hypertension. The production of ROS is increased in numerous conditions that cause vascular disease, including hypercholesterolemia, diabetes, hypertension, smoking and aging. It has also become evident that the major sources of ROS in vascular and non-vascular cells are the NADPH oxidases which are present in many relevant organs, including the vessel, the kidney and the brain. Preliminary studies suggest that the T cell is essential for hypertension caused by angiotensin II and may explain how activation of the NADPH oxidases in various organs, such as the brain leads to hypertension. The effects of angiotensin II on the central nervous system have long been known to contribute to sustained hypertension and recent work from others suggests that angiotension II causes hypertension via a ROS mediated mechanism, involving the NADPH oxidase in the circumventricular organs of the brain. The overall goal of this proposal is to investigate whether the CNS actions of angiotensin II contributes to T cell activation of NADPH oxidases and increased generation of ROS during angiotensin II induced hypertension. I propose that the effects of angiotensin II on the central nervous system can lead to T cell activation. Activated T cells then act on vessels and likely the kidney and via cytokine release stimulate local NADPH oxidases that promote hypertension. In this proposal, I will specifically focus on how angiotensin II may mediate this process via the CNS and I will address the following specific aims to test this hypothesis. Specific aim 1 will examine the role of the CNS in T-cell activation following angiotensin II induced hypertension. Specific aim 2 will determine whether the CNS and the T cell contribute to increased NADPH oxidase activity and reactive oxygen species (ROS) generation caused by angiotensin ll-mediated hypertension. Specific aim 3 will examine the role of the CNS and the T cell in contributing to the vascular dysfunction caused by angiotensin II induced hypertension. To examine these aims I will perform ablation of the anteroventral third ventricle (AV3V) region of the brain and also specifically delete the NADPH oxidase subunit p22phox in the circumventricular organs. The data generated from this proposal will enhance our knowledge of the mechanisms of hypertension as it relates to angiotensin II and will broaden our understanding of the relationships between inflammation, ROS and vascular disease.

描述（由申请人提供）：在过去的 20 年中，人们已经清楚活性氧 (ROS) 在许多血管疾病（包括动脉粥样硬化和高血压）的发生过程中发挥着重要作用。在许多导致血管疾病的情况下，包括高胆固醇血症、糖尿病、高血压、吸烟和衰老，ROS 的产生都会增加。很明显，血管和非血管细胞中ROS的主要来源是NADPH氧化酶，其存在于许多相关器官中，包括血管、肾脏和大脑。初步研究表明，T 细胞对于血管紧张素 II 引起的高血压至关重要，并可能解释大脑等多种器官中 NADPH 氧化酶的激活如何导致高血压。人们早就知道血管紧张素 II 对中枢神经系统的影响会导致持续性高血压，最近其他人的研究表明，血管紧张素 II 通过 ROS 介导的机制引起高血压，涉及大脑室周器官中的 NADPH 氧化酶。该提案的总体目标是研究血管紧张素 II 的 CNS 作用是否有助于 T 细胞激活 NADPH 氧化酶并在血管紧张素 II 诱导的高血压期间增加 ROS 的产生。我认为血管紧张素 II 对中枢神经系统的作用可以导致 T 细胞激活。然后，激活的 T 细胞作用于血管，也可能作用于肾脏，并通过细胞因子释放刺激局部 NADPH 氧化酶，从而促进高血压。在本提案中，我将特别关注血管紧张素 II 如何通过中枢神经系统介导这一过程，并且我将提出以下具体目标来检验这一假设。具体目标 1 将检查 CNS 在血管紧张素 II 诱导的高血压后 T 细胞激活中的作用。具体目标 2 将确定 CNS 和 T 细胞是否有助于血管紧张素 II 介导的高血压引起的 NADPH 氧化酶活性和活性氧 (ROS) 生成的增加。具体目标 3 将检查 CNS 和 T 细胞在血管紧张素 II 诱导的高血压引起的血管功能障碍中的作用。为了检验这些目标，我将对大脑的前腹侧第三脑室 (AV3V) 区域进行消融，并专门删除脑室周围器官中的 NADPH 氧化酶亚基 p22phox。该提案产生的数据将增强我们对与血管紧张素 II 相关的高血压机制的了解，并将拓宽我们对炎症、ROS 和血管疾病之间关系的理解。