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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要心血管疾病 (CVD) 是美国的首要死因，而衰老是一个独立的原因随着人口老龄化的扩大，预计到 2030 年，超过 40% 的人口将面临 CVD 的危险因素。患有CVD的人年老时伴随着内皮依赖性扩张（EDD）减弱、血管内皮细胞减少。一氧化氮 (NO) 生物利用度和大动脉僵硬度增加，是导致动脉粥样硬化风险的重要因素。炎症在这些过程中起着重要作用，但确切的联系尚不清楚。确定 T 细胞是否在与年龄相关的慢性动脉炎症中发挥作用的转化方法首先，我们发现随着衰老，促炎性 T 细胞会在周围积聚。动脉和与年龄相关的动脉功能障碍恶化为了测试这一点，我们将评估动脉功能、免疫。 T 细胞完整、耗尽或受到抑制的年轻和年老小鼠的细胞浸润和炎症亚型。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、衰老动脉中 T 细胞募集的增加，或两者兼而有之。坚持认为来自老年人类捐赠者的 T 细胞将归巢于人源化免疫缺陷的血管系统小鼠并诱发炎症和随后的动脉功能障碍为了检验这一假设，我们将采用过继性方法。将年轻和老年健康人类捐赠者的 T 细胞转移至年轻和老年 NOD-scid/γcnull/A2 人源化小鼠并评估免疫细胞浸润、炎症、动脉功能和 ROS。抑制 T 细胞活化将改善老年人的动脉功能为了检验这一假设，我们将进行评估。老年人血管功能以及内皮细胞和 T 细胞炎症表型前后使用安慰剂或 T 细胞抑制剂 Abatacept 进行治疗这些研究的结果将提供对治疗的深入了解。与年龄相关的动脉功能障碍的病因学，并确定以前未探索的诊断目标和干预的重要目标是维持老年人的心血管健康。