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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：
10557181
负责人：
Anthony John Donato
金额：
$ 44.76万
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 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557181
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 Engraftment Etiology Flow Cytometry Free Radicals Functional disorder Future Genetic Genetic Models Goals Home Human Hypertension Immune Immune system Immunodeficient Mouse Inflammation Inflammatory Intervention Link Mediating Mus Nitric Oxide 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 infiltration T cell therapy T-Cell Activation T-Lymphocyte Testing Tissues 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 immune cell infiltrate improved inhibitor innovation insight mouse model novel pharmacologic 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.

项目总结/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/γcnull/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。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Heterozygosity for ADP-ribosylation factor 6 suppresses the burden and severity of atherosclerosis.

DOI：
10.1371/journal.pone.0285253
发表时间：
2023
期刊：
PLOS ONE
影响因子：
3.7
作者：
Gogulamudi, Venkateswara R.;Islam, Md Torikul;Durrant, Jessica R.;Adeyemo, Adelola O.;Trott, Daniel W.;Hyuhn, Mi Ho;Zhu, Weiquan;Donato, Anthony J.;Walker, Ashley E.;Lesniewski, Lisa A.
通讯作者：
Lesniewski, Lisa A.