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，伴随而来的是 炎症，损害骨骼肌。为身体活动提供动力的肌肉发挥的作用要大得多 动态作用在新陈代谢和炎症中的作用比以前更早认识到，而且很难在儿童中研究 慢性病。我们最重要的假设是，增加体力活动将改善长期的 早期炎症性侮辱的影响。我们将关注哮喘和肥胖症如何影响肌肉，使用 以在儿童身上不可行的方式建立小鼠模型。我们将探索通过哪些机制 运动训练可以缓解慢性儿童疾病的恶性循环，在这种疾病中，缺乏运动 加剧与疾病相关的炎症，进一步损害肌肉和儿童的运动能力。这个 老鼠寿命的缩短使我们能够检查早期炎症的长期影响。模仿，模仿 炎症分别与儿童哮喘和肥胖有关，我们已经 建立卵清蛋白敏化、激发和新生儿过度喂养的小鼠模型。耐人寻味 不同品系的大鼠对肺损伤和肥胖的反应差异--有些会发生全身炎症，而 其他的则不会--将帮助我们分离早期全身性炎症的特定机制。最后，将重点放在一个 这一机制正在成为哮喘和肥胖症过度炎症的关键共同原因， 我们将使用常压缺氧室研究发作性缺氧(EH)。小说，最近出版 我们实验室的方法，基于小鼠的自然行为，将被用来增加体力 将在成年大鼠身上评估其在生命早期的活动及其对炎症和肌肉的影响。两国关系 在肌肉大小、表型和功能的改变中，将被用来解释炎症性改变 相关的细胞和分子机制。我们已经瞄准了将增长和 肌肉炎症，即胰岛素样生长因子-L、胰岛素和白细胞介素6家族 生长因子和细胞因子，以及相关的介质(例如，细胞因子信号转导的抑制因子，核因子-kB)。我们 假设已知的对缺氧和炎症反应的表观遗传机制起作用 在疾病对肌肉的直接影响和对细胞记忆因素的直接影响中都发挥了重要作用 解释在生命早期发生的生理干扰的长期影响。因此，我们将研究 已知的肌肉相关microRNAs(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(MHCs、IGF-I、IGFBPs、IGF受体)相关的染色质的修饰 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 肌肉越来越发达。结合项目一和项目二，这些研究将有助于制定以机制为基础的 将运动作为预防或辅助治疗各种慢性儿童疾病的手段。

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.