The Role of CCR10+ Regulatory T Cells In Hypertension

项目摘要 高血压是全世界死亡和残疾调整生命年的主要原因。尽管目前 在大约50%的高血压患者中，血压仍然不受控制，甚至 在充分控制血压的情况下，心血管事件的风险仍然升高。因此，有一个重大的未解决问题， 需要新的高血压治疗选择。新出现的证据表明，免疫系统 系统在高血压发病机制中的作用。被称为调节性T细胞（Tcells）的免疫细胞亚群是一种免疫调节细胞。 因为它起抑制作用以限制炎症，所以是有吸引力的治疗靶点。然而，最近的证据表明， 提示TGFAP可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， 表达C-C基序趋化因子受体10（CCR 10）在高血压患者的循环中选择性降低， 在高血压小鼠皮肤中增加。鉴于最近有证据表明， 皮肤微血管稀疏（定义为微血管的损失）在高血压中的作用，这些结果表明， CCR 10 + TcR、皮肤微血管和高血压发展之间的新联系。了解一个 为了研究这些效应的机制，我们评估了内皮细胞拉伸增加的效应，如 血压升高，对免疫细胞的影响，并发现CCR 10 + T细胞选择性增加， 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TCR 10在TCR 10中的表达，并促进CCR 10 + Treg向皮肤的募集， 微血管稀疏和高血压发展。这一假设将通过以下方式进行检验： 具体目的：1）验证EC牵张增加通过肿瘤增强TCR 10表达的假设 并确定所得的CCR 10 + T细胞是否迁移和抑制血管生成 在体外响应C-C基序趋化因子配体27（CCL 27）对CCR 10激动，2）确定是否 CCR 10+凝血酶促进皮肤微血管稀疏导致血压升高盐和血管紧张素 II诱导的高血压小鼠体内模型，以及3）测试CCR 10及其皮肤特异性配体CCL 27是否 使用孟德尔随机化的遗传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，以获得进一步的理解和技能， 调节性T细胞和皮肤微血管的研究以及人类遗传方法， 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， 优秀的资源和指导，使申请人成功实现职业目标， 即成为一名独立的医生科学家，照顾高血压患者， 调节性T细胞在这种疾病的发展，以帮助开发新的治疗选择。

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.