The Role of CCR10+ Regulatory T Cells In Hypertension

CCR10 调节性 T 细胞在高血压中的作用

• 批准号: 10427210
• 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
• 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/10427210
• 关键词: Academic Medical Centers; Address; Adoptive Transfer; Agonist; Angiogenesis Inhibition; Angiotensin II; Animal Model; Blood; Blood Circulation; Blood Pressure; Blood flow; CD4 Positive T Lymphocytes; Cardiac; Cause of Death; Cells; Chronic Kidney Failure; Conflict (Psychology); 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; angiogenesis; base; beta-Chemokines; blood pressure control; blood pressure elevation; cardiovascular risk factor; career; chemokine; chemokine receptor; density; disability-adjusted life years; experimental study; genetic approach; hypertensive; in vivo Model; insight; mortality; mouse model; new therapeutic target; normotensive; novel; novel therapeutics; recruit; response; skills; therapeutic target

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.

项目摘要 高血压是全球死亡和残疾调整后的生活年的主要原因。尽管目前 在大约50％的患有高血压的人甚至 通过对BP的足够控制，仍然存在心血管事件的风险升高。因此，有一个重大的未满足 需要新的治疗选择来进行高血压。新兴证据表明免疫的重要作用 高血压发病机理中的系统。称为调节T细胞（Tregs）的免疫细胞子集是 有吸引力的治疗目标，因为它起着抑制炎症的抑制作用。但是，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。该应用程序提供的新证据表明Treg的亚群 在高血压的循环中，表达C-C基序趋化因子受体10（CCR10）有选择地降低 人类和小鼠，在高血压的小鼠皮肤中增加。鉴于最近有重要的证据 皮肤微血管稀疏（定义为微血管丧失）在高血压中的作用，这些结果表明 CCR10+ Treg，皮肤微血管和高血压发育之间的新型联系。理解一个 这些作用的机制，我们评估了内皮细胞伸展增加的影响，如 血压升高，在免疫细胞上，发现CCR10+ Treg选择性地增加了 内皮伸展。因此，在此应用中的研究将检验以下假设，即内皮细胞拉伸增加 增强Treg中的CCR10表达，并促进CCR10+ Treg募集到皮肤以增强 微血管稀疏和高血压发育。该假设将通过以下测试 具体目的：1）检验以下假设，即增加EC拉伸可通过肿瘤增强Treg中的CCR10表达 坏死因子alpha并确定所得的CCR10+ Treg是否转移并抑制血管生成 响应C-C基序趋化因子配体27（CCL27）的CCR10激动剂，2）是否确定是否是否 CCR10+ Tregs促进皮肤微血管稀疏，导致盐和血管紧张素的血压升高 II诱导的高血压小鼠模型在体内和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学方法促进人类的高血压。执行 概述的实验将为申请人提供一个平台，以获得与 调节性T细胞和皮肤微举行的研究以及人类遗传方法（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 杰出的资源和指导能够成功实现申请人的职业目标， 即成为一名独立的医师科学家，照顾患有高血压患者并研究角色 在这种疾病开发中的调节T细胞，以帮助开发新的治疗方法。