Role of Autophagy in Vascular Endothelial Dysfunction with Aging

自噬在衰老引起的血管内皮功能障碍中的作用

基本信息

批准号：
8267242
负责人：
Thomas LaRocca
金额：
$ 2.97万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-07 至 2012-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Aging is associated with the development of vascular endothelial dysfunction characterized by impaired endothelium-dependent dilation (EDD), an independent predictor of cardiovascular disease risk. Although impaired EDD is associated with oxidative stress and chronic low-grade inflammation, the mechanisms by which these processes develop with aging and strategies that can be employed to prevent them are incompletely understood. One unexplored hypothesis is that impairments in the regulation and/or cellular machinery of autophagy underlie the development of vascular endothelial dysfunction (reduced EDD) with aging. Autophagy, the major process by which cells catabolize damaged macromolecules and organelles, inhibits oxidative stress and inflammation and is associated with enhanced longevity. However, its potential role in mediating age-associated vascular endothelial dysfunction is entirely unknown. Accordingly, the goal of this research training project is to determine the role of autophagy in age-related vascular endothelial dysfunction, and to establish the efficacy of an intervention for restoring function. To accomplish this, I will use a novel integrative translational experimental approach that links biochemical and physiological (functional) observations in vitro, ex vivo and in vivo. Specifically, I will assess age-related differences in markers/regulators of autophagy and vascular endothelial function in cell culture, mice, and human subjects. I will also examine relations between autophagy, EDD and oxidative stress/inflammation. Finally, I will determine the efficacy of an intervention designed to stimulate autophagy and restore endothelial function with aging in mice. These results will provide novel and clinically important insight regarding the mechanisms mediating the age-related decline in vascular endothelial function.

描述（由申请人提供）：衰老与血管内皮功能障碍的发生有关，其特征是内皮依赖性扩张（EDD）受损，而内皮依赖性扩张是心血管疾病风险的独立预测因子。尽管 EDD 受损与氧化应激和慢性低度炎症有关，但这些过程随着衰老而发展的机制以及可用于预防它们的策略尚不完全清楚。一种未经探索的假设是，自噬调节和/或细胞机制的损伤是随着衰老而发生血管内皮功能障碍（EDD 减少）的基础。自噬是细胞分解代谢受损大分子和细胞器的主要过程，可抑制氧化应激和炎症，并与延长寿命有关。然而，其在介导与年龄相关的血管内皮功能障碍中的潜在作用尚不清楚。因此，该研究培训项目的目标是确定自噬在与年龄相关的血管内皮功能障碍中的作用，并确定恢复功能的干预措施的功效。为了实现这一目标，我将使用一种新颖的综合转化实验方法，将体外、离体和体内的生化和生理（功能）观察联系起来。具体来说，我将评估细胞培养物、小鼠和人类受试者中自噬和血管内皮功能的标记物/调节因子与年龄相关的差异。我还将研究自噬、EDD 和氧化应激/炎症之间的关系。最后，我将确定旨在刺激自噬并随着小鼠衰老恢复内皮功能的干预措施的功效。这些结果将为介导年龄相关血管内皮功能下降的机制提供新颖且具有临床意义的见解。