EXERCISE TRAINING IN CHILDREN: MECHANISM OF ALLAYING INFLAMMATION IN OBESITY

炎症介质和先天免疫细胞在动脉粥样硬化的发生发展中起着重要作用。随着儿童肥胖症（一种慢性炎症状态）的持续流行，动脉粥样硬化的前体在儿科人群中变得惊人地明显。在我们的理解中存在着深刻的差距：1）为以后的生活中的动脉粥样硬化奠定基础的机制，以及2）如何在早期阶段预防肥胖相关的血管损伤。新的见解表明，体育活动改善内皮损伤的部分原因是通过运动对中性粒细胞和单核细胞的影响，这些细胞是先天免疫的第一反应细胞。使用10周的运动训练干预，一个量身定制的儿童的能力，我们将测试以下假设在肥胖儿童： 1)嗜中性粒细胞和单核细胞的基因组和表观遗传调节以及伴随的生物学功能是过度促炎的，即使在休息时也是如此; 2）运动训练计划将减弱这些细胞的促炎性并增强抗炎性特征; 3）嗜中性粒细胞和单核细胞中肥胖的有害作用的运动训练逆转将在全身、整个生物体水平上平行于关键的生理学变化。我们的招募旨在包括SES较低的儿童，他们患肥胖症及其并发症的风险较高。为了阐明潜在的细胞机制，我们将研究肥胖相关的细胞环境损伤（改变碳水化合物代谢和血脂异常）如何影响中性粒细胞和单核细胞功能。 这将通过使用短暂的运动作为体内急性细胞刺激结合体外细胞培养研究来实现。中性粒细胞和单核细胞的研究将伴随着系统生理功能和训练适应性的稳健指标，使用运动气体交换反应的复杂测量和身体成分的DXA评估。使用创新的、非侵入性的血管反应性测试（闭塞后血管舒张的激光多普勒测量），我们将以一种在儿童中可行的方式间接估计内皮功能。最后，越来越多的人认识到，间歇性缺氧[睡眠呼吸障碍（SDB）和阻塞性睡眠呼吸暂停的结果]会加剧炎症，在肥胖儿童中很常见，并且在与儿童肥胖相关的许多健康和认知障碍中起着重要作用。因此，我们将使用最先进的睡眠研究来评估我们队列中的SDB，并确定其与运动训练干预的细胞和全身反应的相互作用。尽管许多努力实施广泛的体育活动和其他生活方式干预计划，儿童肥胖仍然是一个棘手的问题。我们在这一领域的大量经验表明，需要有针对性的方法：1）确定特定的疾病风险机制，2）证明拟议的干预措施对这些机制的影响。这项研究的结果将有助于将稀缺的资源引导到最需要的肥胖儿童身上。

It is now well recognized that inflammatory mediators and innate immune cells play essential roles in the development and progression of atherosclerosis. With the ongoing epidemic of childhood obesity (a chronic inflammatory state), precursors of atherosclerosis are becoming alarmingly apparent in the pediatric population. There is a profound gap in our understanding of: 1) mechanisms that set the stage for atherosclerosis later in life, and 2) how to prevent obesity-related vascular damage at the earliest stages. New insights suggest that physical activity ameliorates endothelial damage in part through the effect of exercise on neutrophils and monocytes, first-responding cells of innate immunity. Using a 10-week exercise-training intervention, one tailored to the capabilities of the child, we will test the following hypotheses in obese children: 1) neutrophil and monocyte genomic and epigenetic regulation and accompanying biological functions are excessively pro-inflammatory, even at rest; 2) the exercise- training program will attenuate pro-inflammatory and intensify anti-inflammatory profiles of these cells; 3) the exercise training reversal of deleterious effects of obesity in neutrophils and monocytes will parallel key physiological changes at the systemic, whole-organism level. Our recruitment is designed to include lower SES children who are at increased risk for obesity and its complications. To elucidate underlying cellular mechanisms, we will study how obesity-related impairments in the cellular milieu (altered carbohydrate metabolism and dyslipidemia) atfect neutrophil and monocyte function. This will be accomplished by using brief bouts of exercise as an in vivo acute cell stimulus combined with in vitro cell culture studies. The investigation of neutrophils and monocytes will be accompanied by robust metrics of systemic physiological function and adaptability to training using sophisticated measures of the gas exchange response to exercise and DXA assessments of body composition. Using innovative, noninvasive tests of vascular reactivity (laser-doppler measurement of post-occlusive vasodilation), we will indirectly estimate endothelial function in a way that is feasible in children. Finally, it is increasingly recognized that episodic hypoxia [the result of sleep-disordered breathing (SDB) and obstructive sleep apnea] exacerbates inflammation, is common in obese children, and plays a major role in the many health and cognitive impairments associated with childhood obesity. Consequently, we will use state-of-the-art sleep studies to gauge SDB in our cohort and determine its interaction with the cellular and systemic response to the exercise training intervention. Despite many efforts to implement broad programs of physical activity and other lifestyle interventions, pediatric obesity remains an intractable problem. Our considerable experience in this field suggests the need for targeted approaches that: 1) identify specific disease risk mechanisms, and 2) demonstrate an impact of the proposed intervention on those mechanisms. The results of the proposed research will help channel scarce resources toward the obese children with the greatest need.