The Role of CCR10+ Regulatory T Cells In Hypertension

CCR10 调节性 T 细胞在高血压中的作用

基本信息

批准号：
10630113
负责人：
Matthew R Alexander
金额：
$ 15.84万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-20 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630113
关键词：
Academic Medical Centers Address Adoptive Transfer Angiogenesis Inhibition Angiotensin II Animal Model Aorta Blood Blood Pressure Blood Vessels Blood flow CD4 Positive T Lymphocytes Cardiac Cause of Death Cells Chronic Kidney Failure Circulation Coculture Techniques Control Animal Coronary Arteriosclerosis Cytometry Development Disease Endothelial Cells Endothelium Event Exposure to Fibrosis Goals Heart failure Hepatocyte Human Human Genetics Hypertension Immune Immune system In Vitro Individual Inflammation Inflammatory Insulin-Dependent Diabetes Mellitus Knowledge Ligands Link Mechanics Mendelian randomization Mentorship Modeling Morbidity - disease rate Mus Myocardial Ischemia Pathogenesis Pathogenicity Patient Care Patients Periodicity Peripheral Blood Mononuclear Cell Phenotype Physicians Play Population Pulmonary Fibrosis Regulatory T-Lymphocyte Research Resources Risk Factors Rodent Role Scientist Skin Sodium Chloride Stretching Stroke T-Lymphocyte Subsets TNF gene Testing Umbilical vein Vascular resistance Work adaptive immunity beta-Chemokines blood pressure control blood pressure elevation cardiovascular risk factor career chemokine chemokine receptor density disability-adjusted life years experimental study gamma-Chemokines genetic approach hypertensive in vivo Model insight migration mortality mouse model new therapeutic target normotensive novel novel therapeutics recruit response skills therapeutic target

项目摘要

Project Summary Hypertension is the leading cause of death and disability-adjusted life years worldwide. Despite current therapies blood pressure remains uncontrolled in approximately 50% of individuals with hypertension, and even with adequate control of BP an elevated risk of cardiovascular events remains. Hence, there is a major unmet need for new therapeutic options for hypertension. Emerging evidence suggests an important role for the immune system in the pathogenesis of hypertension. An immune cell subset termed regulatory T cells (Tregs) is an attractive therapeutic target as it plays a suppressive role to limit inflammation. However, recent evidence suggests that Tregs can play pathogenic roles in heart failure and lung fibrosis through inhibiting angiogenesis and promoting fibrosis. Novel evidence provided with this application suggests that a subpopulation of Tregs expressing C-C motif chemokine receptor 10 (CCR10) is selectively decreased in the circulation of hypertensive humans and mice and is increased in the skin of mice with hypertension. Given recent evidence for an important role for skin microvascular rarefaction (defined as loss of microvessels) in hypertension, these results suggest a novel link between CCR10+ Tregs, skin microvessels, and hypertension development. To understand a mechanism for these effects, we evaluated the effects of increased endothelial cell stretch, as occurs with elevated blood pressure, on immune cells and found that CCR10+ Tregs are selectively increased with enhanced endothelial stretch. Thus, studies in this application will test the hypothesis that increased endothelial cell stretch augments CCR10 expression in Tregs and promotes CCR10+ Treg recruitment to the skin to enhance microvascular rarefaction and hypertension development. This hypothesis will be tested with the following specific aims: 1) to test the hypothesis that increased EC stretch enhances CCR10 expression in Tregs via tumor necrosis factor alpha and to determine whether resultant CCR10+ Tregs transmigrate and inhibit angiogenesis in response to CCR10 agonism by C-C motif chemokine ligand 27 (CCL27) in vitro, 2) to determine whether CCR10+ Tregs promote skin microvascular rarefaction leading to elevated blood pressure in salt and angiotensin II-induced hypertensive mouse models in vivo, and 3) to test whether CCR10 and its skin-specific ligand CCL27 promote hypertension in humans using a genetic approach of Mendelian randomization. Execution of the outlined experiments will provide a platform for the applicant to gain further understanding and skills related to the study of regulatory T cells and skin microvasculature as well as human genetic approaches such as Mendelian randomization. This work will be performed at Vanderbilt University Medical Center which has outstanding resources and mentorship to enable successful attainment of the career goals of the applicant, namely to become an independent physician scientist caring for patients with hypertension and studying the role of regulatory T cells in development of this disease to help develop new therapeutic options for treatment.

项目概要高血压是全世界死亡和伤残调整生命年的主要原因。尽管目前大约 50% 的高血压患者的血压仍未得到控制，甚至即使血压得到充分控制，心血管事件的风险仍然升高。因此，还有一个重大未满足的问题需要新的高血压治疗选择。新的证据表明免疫的重要作用高血压发病机制中的系统。称为调节性 T 细胞 (Treg) 的免疫细胞亚群是有吸引力的治疗靶点，因为它发挥抑制炎症的作用。然而，最近的证据表明Tregs可以通过抑制血管生成在心力衰竭和肺纤维化中发挥致病作用并促进纤维化。本申请提供的新证据表明 Tregs 亚群表达 C-C 基序趋化因子受体 10 (CCR10) 在高血压循环中选择性减少人类和小鼠中，高血压小鼠皮肤中的含量增加。鉴于最近的证据表明一个重要的皮肤微血管稀疏（定义为微血管损失）在高血压中的作用，这些结果表明 CCR10+ Tregs、皮肤微血管和高血压发展之间的新联系。要了解一个为了了解这些效应的机制，我们评估了增加内皮细胞拉伸的效应，如血压升高对免疫细胞的影响，发现 CCR10+ Tregs 选择性增加内皮拉伸。因此，本申请中的研究将检验增加内皮细胞拉伸的假设增强 Tregs 中的 CCR10 表达并促进 CCR10+ Treg 募集至皮肤，以增强微血管稀疏和高血压的发展。该假设将通过以下内容进行检验具体目标：1) 检验增加 EC 拉伸可通过肿瘤增强 Tregs 中 CCR10 表达的假设坏死因子 α 并确定所得 CCR10+ Tregs 是否迁移并抑制血管生成体外响应 C-C 基序趋化因子配体 27 (CCL27) 的 CCR10 激动作用，2) 确定是否 CCR10+ Tregs 促进皮肤微血管稀疏，导致盐和血管紧张素血压升高 II诱导体内高血压小鼠模型，以及3）测试CCR10及其皮肤特异性配体CCL27是否使用孟德尔随机化的遗传方法促进人类高血压。执行概述的实验将为申请人提供一个平台，以进一步了解相关知识和技能调节性 T 细胞和皮肤微血管系统以及人类遗传方法的研究，例如孟德尔随机化。这项工作将在范德比尔特大学医学中心进行，该中心拥有出色的资源和指导，使申请人能够成功实现职业目标，即成为一名独立的医师科学家，照顾高血压患者并研究其作用调节性 T 细胞在这种疾病的发展过程中的作用，以帮助开发新的治疗选择。