The role of the T Cell in the Genesis of Hypertension

我们的研究计划的总体目标是了解在环境中调节血管功能的因素 高血压等疾病。最近，我们观察到氧化应激与炎症有关， 血管功能障碍和高血压。我们已经发现，缺乏T和B的RAG-1小鼠 淋巴细胞，对慢性低剂量血管紧张素II输注 或DOCA盐挑战。此外，过继转移T细胞而非B细胞完全恢复了高血压。 由于这些挑战。因此，T淋巴细胞对于高血压的发展至关重要。我们 初步数据还显示，血管紧张素II刺激T细胞趋化因子受体水平的增加， CCR5及其配体RANTES的血管水平，并且这与CCR5+的显著浸润相关。 T细胞进入血管，特别是外膜周围脂肪和外膜。在我们的项目中，我们将追求 三个目标。在目标1中，我们将确定CCR5/RANTES相互作用在发展中的重要性。 通过在缺乏RANTES或CCR5的小鼠中诱导高血压来治疗高血压和血管功能障碍。 这些研究将使我们能够了解CCR1是否也可能在高血压中发挥作用，并确定CCR1是否在高血压中起作用。 修饰的RANTES（Met-RANTES）可用于防止T细胞浸润到血管中，并减少血液中的 压力我们发现NADPH氧化酶对于T细胞浸润血管是重要的，但尚不清楚是否 这是由内皮、血管平滑肌或脂肪细胞中产生的ROS介导的。到 为了解决这一问题，我们将创造小鼠选择性缺乏NADPH氧化酶亚基p22pft？*在这些细胞中， Cre lox技术和我们已经创建的p22p/JOX基因敲除小鼠。在目标3中，我们将尝试 通过在SCID小鼠中植入人体组织来确定人类T细胞是否归巢于人类脂肪或血管， 一周后进行自体T细胞过继转移。我们还将确定血管紧张素II 刺激人T细胞在人血管或血管周围脂肪中归巢，如果这依赖于反应性T细胞， 氧物种或RANTES。总的来说，这些研究有望提供有关 炎症反应，发生在高血压的设置和有关的病理生理学， 常见病 该项目将与我们的其他PPG项目密切互动。我们正在制造缺乏P22P/10X的小鼠， 达德利博士将使用的特定细胞达德利博士的项目将利用通常 在我们的实验室工作，我们将提供帮助。我们的新研究方向 在与项目2的项目主任韦安德博士和她的合作研究者戈龙齐博士的合作下， 博士Weyand将协助我们在SCID小鼠中进行人体组织植入的研究， 血管紧张素II输注模型进行了实验。我们的项目也将在很大程度上取决于服务 因为我们将严重依赖于O2~和其他ROS的测量， 血管和组织植入物的免疫染色。林博士和他的团队是人体组织的绝佳来源 我们可以在目标3中使用它。最后，托马斯·J·古兹克博士，他一直是埃默里大学的客座教授， 继续担任顾问，并在我们的外部咨询委员会任职。古兹克博士已经被证明是 优秀的合作者。

The overall goal of our research program is to understand factors that modulate vascular function in the setting of diseases such as hypertension. Recently, we made an observation linking oxidant stress with inflammation, vascular dysfunction and hypertension. We have found that RAG-1"'" mice, which lack both T and B lymphocytes, develop a very blunted hypertensive response to either chronic low-dose angiotensin II infusion or DOCA-salt challenge. Moreover, adoptive transfer of T, but not B cells completely restores the hypertensive caused by these challenges. Thus, the T lymphocyte is essential for the development of hypertension. Our preliminary data also show that angiotensin II stimulates an increase in T cell levels of the chemokine receptor CCR5 and vascular levels of its ligand RANTES and that this is associated with a marked infiltration of CCR5+ T cells into the vessel, and in particular the periadventitial fat and the adventitia. In our project, we will pursue 3 aims. In aim 1, we will determine the importance of the CCR5/RANTES interaction in development of hypertension and vascular dysfunction by inducing hypertension in mice lacking either RANTES or CCR5. These studies will allow us to understand if CCR1 might also play a role in hypertension and to determine if a modified RANTES (Met-RANTES) can be used to prevent T cell infiltration into vessels and to reduce blood pressure. We find that the NADPH oxidase is important for T cell infiltration into the vessel, but it is unclear if this is mediated by ROS produced in the endothelium, the vascular smooth muscle or the adipose cells. To address this, we will create mice selectively lacking the NADPH oxidase subunit p22pft?* in these cells using Cre lox technology and mice with floxed p22p/JOX that we have already created. In aim 3, we will attempt to determine if human T cells home to either human fat or vessels by implanting human tissue in SCID mice and performing adoptive transfer of autologous T cells one week later. We will also determine if angiotensin II stimulates human T cell homing in human vessels or perivascular fat and if this is dependent on reactive oxygen species or RANTES. Overall, these studies promise to provide new information about the inflammatory response that occurs in the setting of hypertension and about the pathophysiology of this common disease. This project will interact with our other PPG projects very closely. We are making mice lacking P22P/10X in specific cells that will be used by Drs. Dudley. Dr. Dudley's project will utilize methods that are commonly employed in our laboratory and we will assist with these. Our new research direction has been enormously aided by collaborations with Dr. Weyand, the project director of project 2 and her co-investigator Dr. Goronzy. Dr. Weyand will assist with our studies of human tissue implants in SCID mice and we will provide assistance with angiotensin II infusion models in her experiments. Our project will also greatly depend on the services provided by Cores A and B as we will rely heavily on measurements of O2~ and other ROS and also immunostaining of vessels and tissue implants. Dr. Lin and his team are an excellent source of human tissue which we can use in aim 3. Finally, Dr. Tomasz J. Guzik, who has been a visiting professor at Emory, will continue to serve as a consultant and serve on our external advisory board. Dr. Guzik has proven to be an excellent collaborator.