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

T 细胞对年龄相关血管功能障碍的影响：一种转化方法

• 批准号: 10549068
• 负责人: Anthony John Donato
• 金额: $ 6.25万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10549068
• 关键词: Acute; Adipose tissue; Adoptive Transfer; Aftercare; Aging; Anti-Inflammatory Agents; Aorta; Arteries; Automobile Driving; Biological Availability; Biopsy; Blood Pressure; Blood Vessels; CD3 Antigens; CD8-Positive T-Lymphocytes; Cardiovascular Diseases; Cause of Death; Cell Aging; Cells; Chemotaxis; Chronic; Data; Diagnostic; Early Diagnosis; Elderly; Endothelial Cells; Endothelium; Etiology; Flow Cytometry; Free Radicals; Functional disorder; Future; Genetic; Genetic Models; Goals; Home; Human; Hypertension; Immune; Immune system; Immunodeficient Mouse; Infiltration; Inflammation; Inflammatory; Intervention; Link; Mediating; Mus; Nitric Oxide; Pharmacology; Pharmacotherapy; Phenotype; Physiologic pulse; Placebos; Plasma; Play; Population; Process; Quantitative Reverse Transcriptase PCR; Reactive Oxygen Species; Resistance; Rodent Model; Role; Spin Trapping; Sterility; T cell therapy; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Tumor-infiltrating immune cells; United States; Vascular Diseases; Western Blotting; age related; aged; aging population; arterial stiffness; brachial artery; burden of illness; cardiovascular disorder risk; cardiovascular health; cardiovascular risk factor; cell age; cytokine; healthy aging; humanized mouse; improved; inhibitor; innovation; insight; mouse model; novel; recruit; response; translational approach; translational study

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.

项目摘要/摘要 心血管疾病(CVD)是美国人的主要死亡原因，老龄化是独立的 心血管疾病的危险因素。随着老龄化人口的扩大，到2030年，预计将有40%的人口 得了脑血管病。高龄伴随着钝化的内皮依赖性扩张(EDD)， 一氧化氮(NO)的生物利用度和大动脉僵硬增加，是心血管风险的重要贡献者。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。我们将利用一个 翻译方法确定T细胞是否在年龄相关性慢性动脉炎症中发挥作用 随后出现功能障碍。首先，我们假设，随着年龄的增长，促炎T细胞在周围积累 并加重与年龄相关的动脉功能障碍。为了测试这一点，我们将评估动脉功能，免疫 T细胞完整、耗尽或抑制的幼年和老年小鼠的细胞浸润和炎症亚型。在……里面 此外，我们将采用收养转移来确定年龄相关的动脉功能障碍是否由 固有的与年龄相关的T细胞变化，增加T细胞对老年动脉的募集，或两者兼而有之。第二，我们 假设来自老年人类捐赠者的T细胞将是人源化免疫缺陷患者血管系统的归宿 并导致炎症和随后的动脉功能障碍。为了检验这一假设，我们将采用 将健康青年和老年供者的T细胞移植到NOD-SCID/γ/A2人源化的青年和老年 并评估免疫细胞渗透、炎症、动脉功能和ROS。第三，我们假设 抑制T细胞激活将改善老年人的动脉功能。为了检验这一假设，我们将评估 老年人治疗前后血管功能及内皮细胞和T细胞炎症表型 使用安慰剂或T细胞抑制剂abatacept治疗。这些研究的结果将为我们提供对 年龄相关性动脉功能障碍的病因，并确定以前未探索的诊断和 以维护老年人心血管健康为重要目标的干预。