The Role of CCR10+ Regulatory T Cells In Hypertension

项目摘要 高血压是世界范围内死亡和伤残调整寿命年的主要原因。尽管目前 治疗方法在大约50%的高血压患者中血压仍然没有得到控制，甚至 在充分控制BP的情况下，心血管事件的风险仍然增加。因此，有一个重大的未满足 需要为高血压提供新的治疗选择。新出现的证据表明，免疫力在 系统在高血压发病机制中的作用。一种称为调节性T细胞(Tregs)的免疫细胞亚群 有吸引力的治疗靶点，因为它起到抑制炎症的作用。然而，最近的证据表明 提示Tregs可能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。 和促进纤维化。这项申请提供的新证据表明，特雷格人的一个亚群 C-C基序趋化因子受体10在高血压循环中的表达选择性降低 并在高血压小鼠的皮肤中增加。鉴于最近的证据表明 皮肤微血管稀疏(定义为微血管丢失)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生之间的新联系。要了解一个 这些影响的机制，我们评估了增加内皮细胞拉伸的影响，如发生在 血压升高，对免疫细胞的影响，发现CCR10+Tregs随着增强而选择性增加 血管内皮细胞拉伸。因此，这一应用中的研究将检验这样一个假设，即增加内皮细胞伸展 增强CCR10在Treg中的表达并促进CCR10+Treg在皮肤中的募集，以增强 微血管疏松与高血压的发生发展。这一假设将用以下方法进行检验 具体目的：1)验证增加EC拉伸通过肿瘤增强Tregs中CCR10表达的假说 并确定产生的CCR10+Tregs是否迁移和抑制血管生成 C-C基序趋化因子配体27(CCL27)体外对CCR10激动剂的反应，2)确定 CCR10+Tregs促进皮肤微血管疏松，导致盐和血管紧张素的血压升高 2)建立体内高血压小鼠模型；3)检测CCR10及其皮肤特异性配体CCL27 使用孟德尔随机化的遗传方法促进人类高血压。签立 概述的实验将为申请者提供一个平台，以获得与以下相关的进一步理解和技能 调节性T细胞和皮肤微血管以及人类遗传途径的研究，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，使申请人能够成功地实现职业目标， 即成为一名独立的内科科学家，关心高血压患者并研究其作用 研究调节性T细胞在这种疾病的发展中的作用，以帮助开发新的治疗方案。

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.