Aging, Western Diet and Endothelial Dysfunction: Role of NFkB and JNK Activation

衰老、西方饮食和内皮功能障碍：NFkB 和 JNK 激活的作用

基本信息

批准号：
8136352
负责人：
Lisa A Lesniewski
金额：
$ 13.54万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-15 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8136352
关键词：
Adult Adverse effects Age Aging Animals Apoptosis Apoptotic Atherosclerosis Behavior Biological Availability Blood Vessels Boxing Carotid Arteries Clinical Trials Consumption Custom Data Development Diabetes Mellitus Diet Disease Elderly Endothelium Environmental Risk Factor Exposure to Fatty acid glycerol esters Functional disorder Future Goals Human Inflammation Inflammatory Intervention JUN gene Life Style Measures Metabolic Molecular Mus NF-kappa B Nitric Oxide Oxidative Stress Phenotype Physiological Regulation Resistance Role Signal Pathway Signal Transduction Signaling Molecule Testing Tissues United States National Institutes of Health Work base cardiovascular disorder risk disorder risk feeding insight male middle age novel obesity risk prevent public health relevance stress-activated protein kinase 1 vascular endothelial dysfunction vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Advancing age is associated with the development of vascular dysfunction and disease. However, the mechanisms involved are incompletely understood. One novel and largely unexplored hypothesis is that "physiological resistance" to the adverse effects of common environmental factors to which we are chronically exposed decreases with aging, thus exacerbating the resulting dysfunction and increased risk of disease. One such factor may be a "Western", i.e., high-fat, diet (WD). The overall goal of this project is to examine the mechanisms by which WD exacerbates age-associated vascular endothelial dysfunction. Specifically, we will examine the effect of WD on signaling pathways involved in the regulation of vascular inflammation, oxidative stress and apoptosis in middle-aged (MA) and older (O) mice. The specific aims are (1) to measure endothelium dependent dilation (EDD) and nitric oxide (NO) bioavailability in the carotid arteries of MA/O mice, to determine if advancing age is associated with a pro- inflammatory, pro-oxidative, pro-apoptotic phenotype, (2) to determine if WD increases the activation of the pro-inflammatory and apoptotic signaling molecules; nuclear factor kappa B (NFkB), c-jun NH2 terminal kinase (JNK), and forkhead box O (FoxO) in MA/O mice and (3) to determine if inhibition of NFkB or JNK can reverse WD-associated vascular dysfunction, inflammation, oxidative stress and apoptosis in MA/O mice. To do so, we will study young (Y: 6-8 mo), MA (18-20 mo) and O (30-32 mo) male B6D2F1 mice. Mice will be fed standard chow (NCD, 12% kcal from fat) or a custom WD (40% kcal from fat). Vascular endothelial function will be measured in isolated carotid arteries. Nitric oxide bioavailability and activation of NFkB, JNK and FoxO will be assessed in aortic lysates. Lastly, we will utilize pharmacological inhibition of NFkB and JNK to determine their roles in WD-associated vascular endothelial dysfunction, inflammation, oxidative stress and apoptosis in MA/O mice. The expected results will provide novel insight into the mechanisms by which WD exacerbates age-associated vascular dysfunction. PUBLIC HEALTH RELEVANCE: Advancing age and consumption of a WD are associated with vascular dysfunction and disease. This proposal aims to determine if the adverse effects of WD become greater with advancing age and the mechanisms by which this may occur.

描述（由申请人提供）：增长年龄与血管功能障碍和疾病的发展有关。但是，涉及的机制尚不完全理解。一种新颖且在很大程度上没有探索的假设是，我们长期暴露的常见环境因素的不利影响随着衰老而降低，从而加剧了由此导致的功能障碍和疾病风险增加。这样的因素之一可能是“西方”，即高脂，饮食（WD）。该项目的总体目标是检查WD加剧与年龄相关的血管内皮功能障碍的机制。具体而言，我们将研究WD对中年（MA）和年龄较大（O）小鼠血管炎症，氧化应激和凋亡的调节的信号通路的影响。 The specific aims are (1) to measure endothelium dependent dilation (EDD) and nitric oxide (NO) bioavailability in the carotid arteries of MA/O mice, to determine if advancing age is associated with a pro- inflammatory, pro-oxidative, pro-apoptotic phenotype, (2) to determine if WD increases the activation of the pro-inflammatory and apoptotic signaling molecules; MA/O小鼠中的核因子Kappa B（NFKB），C-Jun NH2末端激酶（JNK）和Forkhead Box O（FoxO）和（3）确定NFKB或JNK的抑制是否可以逆转WD与WD相关的血管功能障碍，炎症，氧化应激，氧化应激，氧化，氧化，氧化和Apoptosis in Ma/o-opopiss in/opoptiss in//o e e e e e s//o n e e n ins/opopiss ins/omice。为此，我们将研究Young（Y：6-8 MO），MA（18-20 mo）和O（30-32 mo）男性B6D2F1小鼠。小鼠将被喂养标准食物（NCD，脂肪含量为12％）或定制WD（脂肪40％kcal）。血管内皮功能将在孤立的颈动脉中测量。一氧化氮的生物利用度和NFKB，JNK和FOXO的激活将在主动脉裂解物中进行评估。最后，我们将利用对NFKB和JNK的药理抑制作用来确定它们在MA/O小鼠中与WD相关的血管内皮功能障碍，炎症，氧化应激和凋亡中的作用。预期的结果将为WD加剧与年龄相关的血管功能障碍的机制提供新的见解。公共卫生相关性：促进WD的年龄和消费与血管功能障碍和疾病有关。该建议旨在确定WD的不利影响是否随着年龄的增长和可能发生的机制而变得更大。