Impact of T cells on age-related vascular dysfunction: A translational approach

项目概要/摘要 心血管疾病（CVD）是美国人死亡的主要原因，衰老是一个独立的原因。 CVD的危险因素。随着人口老龄化的扩大，到2030年，预计将有40%以上的人口 有CVD。高龄伴有内皮依赖性舒张功能（EDD）减弱， 一氧化氮（NO）的生物利用度和大动脉僵硬度的增加是CVD风险的重要因素。动脉 炎症在这些过程中起着重要作用，但确切的联系尚不清楚。我们将利用 翻译方法来确定T细胞是否在年龄相关的慢性动脉炎症中发挥作用， 随后的功能障碍。首先，我们假设随着年龄的增长，促炎性T细胞聚集在 并加剧与年龄相关的动脉功能障碍。为了验证这一点，我们将评估动脉功能，免疫功能， T细胞完整、耗尽或抑制的年轻和老年小鼠中的细胞浸润和炎性亚型。在 此外，我们将采用过继转移来确定与年龄相关的动脉功能障碍是否由以下原因引起： T细胞的内在年龄相关变化、增加的T细胞向老化动脉的募集或两者。二是 假设来自老年人供体的T细胞将归巢于人源化免疫缺陷的血管系统， 并诱导炎症和随后的动脉功能障碍。为了验证这一假设，我们将采用 将来自年轻和老年健康人供体的T细胞转移至年轻和老年NOD-scid/γ cnull/A2人源化细胞 小鼠，并评估免疫细胞浸润、炎症、动脉功能和ROS。第三，我们假设， 抑制T细胞活化将改善老年人的动脉功能。为了验证这一假设，我们将评估 血管功能和内皮细胞和T细胞炎症表型在老年人前后 用安慰剂或T细胞抑制剂阿巴西普治疗。这些研究的结果将提供深入了解 年龄相关动脉功能障碍的病因学，并确定以前未探索的诊断目标， 干预的重要目标是维持老年人的心血管健康。

Project Summary/Abstract Cardiovascular disease (CVD) is the leading cause of death in the United States and aging is an independent risk factor for CVD. With the expansion of the aging population, by 2030 >40% of the population is projected to have CVD. Advanced age is accompanied by blunted endothelium-dependent dilation (EDD), reductions in nitric oxide (NO) bioavailability and increased large artery stiffness, important contributors to CVD risk. Arterial inflammation plays an important role in these processes but the precise link is unclear. We will utilize a translational approach to determine whether T cells play a role in age-related chronic arterial inflammation and subsequent dysfunction. First, we hypothesize that with aging, pro-inflammatory T cells accumulate around arteries and exacerbate age-related arterial dysfunction. To test this, we will assess arterial function, immune cell infiltration and inflammatory subtypes in young and old mice with T cells intact, depleted or inhibited. In addition, we will employ adoptive transfer to determine whether age-related arterial dysfunction results from intrinsic age-related changes to T cells, increased T cell recruitment to the aged artery, or both. Second, we hypothesize that T cells from older human donors will home to the vasculature of humanized immuno-deficient mice and induce inflammation and subsequent arterial dysfunction. To test this hypothesis, we will adoptively transfer T cells from young and older healthy human donors to young and old NOD-scid/γcnull/A2 humanized mice and assess immune cell infiltration, inflammation, arterial function, and ROS. Third, we hypothesize that inhibition of T cell activation will improve arterial function in older adults. To test this hypothesis, we will assess vascular function and endothelial cell and T cell inflammatory phenotype in older humans before and after treatment with placebo or a T cell inhibitor, Abatacept. The results of these studies will provide insight into the etiology of age-related arterial dysfunction and identify previously unexplored targets for diagnostics and intervention with the significant goal of maintaining cardiovascular health in the elderly.