Inflammatory suppression of endothelial function with aging and habitual exercise

衰老和习惯性运动对内皮功能的炎症抑制

• 批准号: 7408790
• 负责人: Ashley Elizabeth Walker
• 金额: $ 2.92万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7408790
• 关键词: Acute; Acute-Phase Proteins; Adult; Aerobic Exercise; Age; Aging; Anti-Inflammatory Agents; Antioxidants; Arteries; Ascorbic Acid; Aspirin; Blood Vessels; Cardiovascular Diseases; Cessation of life; Chronic; Clinical; Development; Disease; Dose; Elderly; Endothelium; Enzymes; Exercise; Genes; Goals; Human; Impairment; Inflammation; Inflammatory; Infusion procedures; Institutes; Intervention; Intravenous; Measurement; Measures; Mediating; Molecular; NF-kappa B; National Research Service Awards; Oxidants; Oxidative Stress; Peripheral; Peripheral Blood Mononuclear Cell; Placebo Control; Placebos; Plasma; Production; Proteins; Public Health; Reactive Oxygen Species; Research; Research Personnel; Research Project Grants; Risk Factors; Signal Transduction; Support of Research; Translational Research; Vascular Endothelial Cell; Walkers; Woman; brachial artery; cardiovascular disorder prevention; career; cytokine; human subject; improved; insight; intravenous administration; men; peer; pre-doctoral; prevent; protein expression; salicylsalicylic acid; sedentary; transcription factor; young adult

DESCRIPTION (provided by applicant): This predoctoral NRSA proposal seeks support for research career development in the emerging, biomedically important field of "vascular aging". The career goal of the candidate, Ms. Walker, is to become an independent investigator in translational research focusing on the mechanisms mediating vascular aging in humans and interventions that prevent or reverse vascular aging. The proposed research project has important clinical implications for the prevention of cardiovascular disease (CVD) because vascular aging is now accepted as a major risk factor CVD. This project will focus on the reduction in vascular endothelial function, a key expression of vascular aging, as determined by measurement of endothelium-dependent dilation (EDO). EDD is markedly reduced with aging, even in healthy older adults, but the underlying mechanisms are incompletely understood. Chronic low-grade inflammation (with associated oxidative stress) is one possible mechanism that has not been directly investigated. In contrast to their sedentary peers, older adults who regularly perform aerobic exercise demonstrate largely preserved EDD. It is unknown if an absence of inflammation and associated oxidative stress-mediated suppression of EDD contributes to the preserved function in habitually exercising older adults. The influence of inflammation and oxidative stress on aging and age-associated diseases is a major research goal of the National Institute on Aging. To investigate these topics, groups of young and older healthy sedentary and habitually exercising men and women will be studied. The influence of inflammation on EDD (brachial artery flow-mediated dilation) will be determined by short-term inhibition of nuclear factor kappa B signaling with orally administered Salsalate, an aspirin-like compound. Intravenous infusion of vitamin C, a potent antioxidant, will be used to determine the effects of oxidative stress on EDD. Additional insight into the cellular and molecular mechanisms involved in age- and exercise-related effects on EDD will be obtained by measurement of circulating markers of inflammation and oxidative stress and gene and/or protein expression of inflammatory molecules, oxidatively modified proteins, and oxidant and antioxidant enzymes in peripheral blood mononuclear cells and vascular endothelial cells from human subjects. The proposed research project has important public health relevance as CVD remains a leading cause of illness and death in the US.

描述（由申请人提供）：这项 NRSA 博士前提案寻求对新兴的生物医学重要领域“血管老化”的研究职业发展的支持。沃克女士的职业目标是成为转化研究领域的独立研究者，重点研究介导人类血管衰老的机制以及预防或逆转血管衰老的干预措施。拟议的研究项目对于预防心血管疾病（CVD）具有重要的临床意义，因为血管老化现在被认为是CVD的主要危险因素。该项目将重点关注血管内皮功能的降低，这是血管衰老的一个关键表现，通过测量内皮依赖性扩张（EDO）来确定。随着年龄的增长，即使是健康的老年人，EDD 也会明显减少，但其潜在机制尚不完全清楚。慢性低度炎症（伴有相关的氧化应激）是一种可能的机制，但尚未得到直接研究。与久坐的同龄人相比，经常进行有氧运动的老年人表现出很大程度上保留了 EDD。目前尚不清楚，缺乏炎症和相关的氧化应激介导的 EDD 抑制是否有助于习惯锻炼的老年人保留功能。炎症和氧化应激对衰老和年龄相关疾病的影响是国家衰老研究所的主要研究目标。为了研究这些主题，将对年轻和年长的健康久坐和习惯锻炼的男性和女性进行研究。炎症对 EDD（肱动脉血流介导的扩张）的影响将通过口服双水杨酸（一种阿司匹林样化合物）对核因子 kappa B 信号传导的短期抑制来确定。静脉输注维生素 C（一种有效的抗氧化剂）将用于确定氧化应激对 EDD 的影响。通过测量炎症和氧化应激的循环标志物以及炎症分子、氧化修饰蛋白和氧化剂的基因和/或蛋白表达，可以进一步了解年龄和运动对 EDD 的影响所涉及的细胞和分子机制。人类受试者外周血单核细胞和血管内皮细胞中的抗氧化酶。拟议的研究项目具有重要的公共卫生意义，因为心血管疾病仍然是美国疾病和死亡的主要原因。