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: 10090548
• 负责人: Anthony John Donato
• 金额: $ 65.14万
• 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/10090548
• 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/antagonist; 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）是美国死亡的主要原因，衰老是独立的 CVD的危险因素。随着老龄化人口的扩大，到2030年，预计人口的40％被预计 有CVD。高龄是通过钝性的内皮依赖性词典（EDD）完成的，减少了 一氧化氮（NO）生物利用度和增加大动脉刚度，这是CVD风险的重要贡献者。动脉 炎症在这些过程中起着重要作用，但精确的联系尚不清楚。我们将利用一个 转化方法来确定T细胞在与年龄相关的慢性动脉注射中是否起作用 随后的功能障碍。首先，我们假设随着衰老，促炎的T细胞积聚 动脉和加剧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细胞完好无损，耗尽或抑制的年轻小鼠和老鼠的细胞浸润和炎症亚型。 此外，我们将采用自适应转移来确定与年龄相关的伪像是由 与年龄相关的固有变化T细胞，增加T细胞对老化动脉的募集或两者兼而有之。第二，我们 假设来自年长的人类捐助者的T细胞将成为人性化免疫缺陷的脉管系统 小鼠并诱导注射和随后的动脉功能障碍。为了检验这一假设，我们将适当 将T细胞从年轻和老年人健康的人类捐助者转移到年轻人和老年人nod-scid/γcnull/a2人源化 小鼠和评估免疫球浸润，注射，动脉功能和ROS。第三，我们假设 T细胞激活的抑制作用将改善老年人的动脉功能。为了检验这一假设，我们将评估 老年人之前和之后，老年人的血管功能以及内皮细胞和T细胞炎症表型 用安慰剂或T细胞抑制剂Abatacept治疗。这些研究的结果将为您洞悉 与年龄相关的动脉功能障碍的病因，并确定以前意外的诊断目标和 干预措施的重大目标是维持老年人的心血管健康。