Inflammatory suppression of endothelial function with aging and habitual exercise

描述(由申请者提供)：这项博士前NRSA提案寻求在“血管老化”这一新兴的、具有重要生物医学意义的领域为研究事业发展提供支持。候选人沃克女士的职业目标是成为转化研究的独立研究员，专注于人类血管老化的调节机制，以及防止或逆转血管衰老的干预措施。该研究项目对预防心血管疾病(CVD)具有重要的临床意义，因为血管老化现在被认为是心血管疾病的主要危险因素。该项目将重点关注血管内皮功能的降低，这是血管老化的关键表现，通过测量内皮依赖性扩张(EDO)来确定。EDD随着年龄的增长而显著减少，即使在健康的老年人中也是如此，但其潜在的机制尚不完全清楚。慢性低度炎症(伴随氧化应激)是一种尚未被直接研究的可能机制。与久坐不动的同龄人相比，经常进行有氧运动的老年人表现出基本保留的EDD。目前尚不清楚，没有炎症和相关的氧化应激介导的EDD抑制是否有助于老年人习惯性运动时保留的功能。炎症和氧化应激对衰老和老年相关疾病的影响是美国国家老龄研究所的主要研究目标。为了调查这些话题，将对健康久坐和习惯锻炼的年轻和年长的男性和女性进行研究。炎症对EDD(臂动脉血流介导的扩张)的影响将通过口服阿司匹林类化合物水杨酸盐对核因子kappa B信号的短期抑制来确定。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，以及受试者外周血单个核细胞和血管内皮细胞中炎症分子、氧化修饰蛋白、氧化剂和抗氧化酶的基因和/或蛋白表达，可以进一步深入了解年龄和运动对EDD影响的细胞和分子机制。这项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。

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.