EXERCISE AND OXIDATIVE STRESS MECHANISMS IN CHILDREN WITH THE METABOLIC SYND

代谢综合征儿童的运动和氧化应激机制

• 批准号: 7077884
• 负责人: dan cooper
• 金额: $ 27.41万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-10 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7077884
• 关键词: antioxidants; biomarker; blood chemistry; breath tests; cardiovascular disorder risk; children; comorbidity; diabetes risk; dietary lipid; exercise; exercise tolerance; free radical oxygen; gender difference; gene expression; human puberty; human subject; leukocyte activation /transformation; metabolic syndrome; molecular dynamics; neutrophil; obesity; oxidative phosphorylation; oxidative stress; pathogenic diet; pathologic process; physical fitness

The metabolic syndrome (MS) is a cluster of metabolic abnormalities [obesity, dyslipidemia, hypertension and hyperglycemia] predisposing to increased incidence of type 2 diabetes and cardiovascular mortality. Alarmingly, the incidence of the MS is insidiously increasing among children and adolescents, setting the stage for unprecedented levels of cardiovascular and metabolic disease in the future, with then potential for staggering morbidity and social costs. Many pathogenetic aspects of the MS are still unclear, but oxidative stress (OS), an imbalance between production of reactive oxygen species (ROS) and antioxidant defenses, is emerging as a major potential mechanism. While physical activity and nutrition are well known naturally occurring modifiers of ROS production and anti-oxidant defenses, in children key mechanisms governing the interactions among exercise, diet, and oxidative pathways, and the influence of these variables on the onset and comorbidities of the MS, have yet to be investigated. The fundamental premise of our research is that physical inactivity, high-fat diet and obesity all conspire to impair the regulation of OS in children. This general hypothesis can be tested using exercise as a quantifiable and reproducible experimental perturbation, due to its unique ability to stimulate, even in brief bouts, two main sources of ROS-- mitochondrial O2 flow and neutrophils (the latter, part of the stress/inflammatory response now known to occur with exercise in children). We propose that each of these key mechanisms (physical inactivity, high fat diet, obesity) impairs the balance between ROS generation and antioxidant defenses, rendering the child more vulnerable to the damaging effects of OS. Children will be challenged with specially designed exercise protocols, while all major variables associated with oxidative activity (oxidation of lipids, glucose, proteins, nitric oxide, DNA; neutrophil oxidative activity and gene expression, systemic antioxidants levels) will be simultaneously monitored. The following specific hypotheses will be tested: a) that even in the healthy child, a marked influence on oxidative processes during exercise is exerted by gender, maturational status and degree of physical fitness; b) that the transient hyperlipidemia caused by a high fat meal can acutely and measurably increase exercise-induced oxidative stress; and c) that pediatric obesity and metabolic syndrome are associated with exaggerated resting and exercise-induced oxidative stress. The PPG is uniquely suited for this challenging project, combining the experiences in pediatric and diabetic exercise testing of our human performance laboratory and metabolic core, with the expertise in oxidative marker analysis of three different laboratories, all collaborating in the project. Based on new and exciting preliminary studies, this research is aimed at defining these previously unexplored mechanisms, optimizing the use of exercise and diet, both diagnostically and therapeutically, to prevent or attenuate the deleterious health consequences of the metabolic syndrome in children.

代谢综合征（MS）是一组代谢异常[肥胖，血脂异常，高血压 和高血糖]倾向于增加2型糖尿病的发生率和心血管死亡率。 令人震惊的是，在儿童和青少年中，MS的发病率正在下降，设定 未来的心血管和代谢疾病的前所未有的阶段 惊人的发病率和社会成本。 MS的许多致病方面仍不清楚，但氧化 压力（OS），反应性氧（ROS）和抗氧化剂防御的产生之间的不平衡， 正在成为主要潜在机制。虽然身体活动和营养自然是众所周知的 发生ROS产生和抗氧化剂防御的修饰符，在儿童的关键机制中 运动，饮食和氧化途径之间的相互作用，以及这些变量对发作的影响 MS的合并症尚未对其进行调查。我们研究的基本前提是 身体上的不活跃，高脂饮食和肥胖都共同损害儿童的OS调节。这 一般假设可以使用练习作为可量化且可重复的实验性检验 扰动由于其独特的刺激能力，即使在短暂的回合中也是ROS-的两个主要来源 - 线粒体O2流量和中性粒细胞（后者，现在已知的应力/炎症反应的一部分 发生在儿童中的运动）。我们建议这些关键机制中的每一种 饮食，肥胖）会损害ROS产生和抗氧化剂防御之间的平衡，使孩子呈现 更容易受到OS的破坏性影响。儿童将通过专门设计的锻炼面临挑战 方案，而所有与氧化活性相关的主要变量（脂质，葡萄糖，蛋白质，氧化 一氧化氮，DNA；中性粒细胞氧化活性和基因表达，全身抗氧化剂水平）将是 同时监视。将测试以下特定假设：a）即使在健康的孩子中， 性别，成熟地位和 身体健康程度； b）高脂餐引起的短暂性高脂血症可能会敏锐而 可测量地增加运动诱导的氧化应激； c）小儿肥胖和代谢 综合征与夸张的静息和运动诱导的氧化应激有关。 PPG是 非常适合这个具有挑战性的项目，结合了儿科和糖尿病运动的经验 测试我们的人类绩效实验室和代谢核心，并具有氧化标记的专业知识 分析三个不同的实验室，所有实验室都在项目中合作。基于新的和令人兴奋的初步 研究，这项研究旨在定义这些以前未开发的机制，优化了使用 诊断和治疗的运动和饮食，以防止或减弱有害健康 儿童代谢综合征的后果。