INFLAMMATION AND PHYSICAL ACTIVITY DURING CRITICAL PERIODS OF DEVELOPMENT

慢性哮喘和肥胖是当今对儿童健康最令人不安的两个威胁， 炎症，损害骨骼肌。肌肉，为身体活动提供动力， 在代谢和炎症中的动态作用比以前认识到的要大，并且很难在患有 慢性病。我们的总体假设是，增加体力活动将改善长期的 早期炎症的影响。我们将重点关注哮喘和肥胖如何影响肌肉， 在儿童中不可行的方法。我们将探索 运动训练可以缓解慢性儿童疾病的“恶性循环”， 加重疾病相关的炎症，进一步损害肌肉和儿童的运动能力。的 大鼠寿命较短，这使我们能够研究早期炎症的长期影响。模仿 分别与儿童哮喘和肥胖症相关的炎症，我们已经 建立了卵清蛋白致敏和激发以及新生儿过度喂养的小鼠模型。耐人寻味 大鼠对肺损伤和肥胖的反应存在品系差异--一些大鼠出现全身性炎症， 其他的则不然--这将帮助我们分离出早期系统性炎症的特定机制。最后，重点放在 这种机制正在成为哮喘和肥胖症过度炎症的一个关键共同原因， 我们将使用常压缺氧室来研究间歇性缺氧（EH）。小说，最近出版 我们实验室的方法，基于大鼠幼崽的自然行为，将用于增加身体 将在成年大鼠中评估其在生命早期的活动及其对炎症和肌肉的影响。的关系 在肌肉大小、表型和功能的变化中， 相关的细胞和分子机制。我们针对的是将增长和 肌肉中的炎症，即胰岛素样生长因子-I（IGF-I）、胰岛素和白细胞介素-6家族， 生长因子和细胞因子，以及相关介质（例如，细胞因子信号传导抑制因子，NF-κ B）。我们 假设已知对缺氧和炎症反应的表观遗传机制， 在疾病对肌肉的直接影响和对细胞记忆因子， 解释生命早期发生的生理扰动的长期影响。因此，我们将研究 已知的肌肉相关microRNA（例如，miR-1和miR-133），并分析DNA甲基化和组蛋白 与可能的靶基因（MHC，IGF-I，IGFBPs，IGF受体）相关的染色质修饰， 新生和青春期动物的肌肉。为了进一步加强PPG的整合，我们将开始 探讨运动和炎症对循环中性粒细胞和单核细胞相互作用的影响 不断增长的肌肉结合项目I和II，这些研究将有助于制定基于机制的 利用运动作为预防或治疗无数慢性儿童疾病的方法。

Chronic asthma and obesity, two of today's most troubling threats to child health, are accompanied by inflammation, which impairs skeletal muscle. Muscle, which powers physical activity, plays a much more dynamic role in metabolism and inflammation than earlier realized, and is difficult to study in children with chronic illness. Our overarching hypothesis is that increases in physical activity will ameliorate the long-term effects of early-life inflammatory insults. We will focus on how asthma and obesity influence muscle, using murine models in ways that would not be feasible in children. We will explore the mechanisms by which exercise-training can mitigate the "vicious cycle" of chronic childhood disease in which physical inactivity exacerbates disease-related inflammation, further impairing muscle and the child's ability to exercise. The shorter lifespan of rats permits us to examine the long-term effects of early-in-life inflammation. To mimic inflammation associated specifically with childhood asthma and obesity, respectively, we have already established murine models of ovalbumin sensitization-and-challenge and neonatal overfeeding. Intriguing strain differences in responses to lung injury and obesity in the rat-some develop systemic inflammation while others do not-will help us isolate the specific mechanisms of early systemic inflammation. Finally, to focus on a mechanism that is emerging as a key common cause of excessive inflammation in both asthma and obesity, we will study episodic hypoxia (EH) using a normobaric hypoxia chamber. Novel, recently published approaches from our laboratory, based on natural behavior of rat pups, will be used to increase physical activity early in life, and its impact on inflammation and muscle will be assessed in adult rats. The relationship among changes in muscle size, phenotype, and function will be used to interpret alterations in inflammatory related cellular and molecular mechanisms. We have targeted specific pathways that link growth and inflammation in muscle, namely the insulin-like growth factor-l (IGF-I), insulin, and interieukin-6 families of growth factors and cytokines, and related mediators (e.g., suppressors of cytokine signaling, NF-KB). We hypothesize that epigenetic mechanisms, which are known to respond to hypoxia and inflammation, play substantial roles in both the immediate impact of disease on muscle and on the cell-memory factors that explain long-term effects of physiological perturbations occurring early in life. Consequently, we will study known muscle-related microRNAs (e.g., miR-1 and miR-133), and analyze DNA methylation and histone modifications in the chromatin associated with the likely target genes (MHCs, IGF-I, IGFBPs, IGF receptor) in muscle in neonatal and adolescent animals. To further enhance the integration of the PPG, we will begin to explore the impact of exercise and inflammation on circulating neutrophils and monocytes in their interaction with growing muscle. In conjunction with Projects I and II, these studies will help develop mechanism-based uses of exercise as preventive or adjunctive therapy for a myriad of chronic childhood diseases.