INFLAMMATION AND PHYSICAL ACTIVITY DURING CRITICAL PERIODS OF DEVELOPMENT

项目描述 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，它们伴随着炎症，这会损害骨骼肌。肌肉为身体活动提供动力，在代谢和炎症中发挥着比以前认识到的更动态的作用，并且很难在患有慢性疾病的儿童中进行研究。我们的首要假设是，增加体力活动将改善早期生活炎症损伤的长期影响。我们将重点关注哮喘和肥胖如何影响肌肉，使用小鼠模型，在儿童中是不可行的。我们将探索运动训练可以减轻慢性儿童疾病的“恶性循环”的机制，在这种疾病中，身体活动不足会加剧疾病相关的炎症，进一步损害肌肉和儿童的运动能力。大鼠的寿命较短，这使我们能够研究早期炎症的长期影响。为了分别模拟与儿童哮喘和肥胖相关的炎症，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。大鼠在肺损伤和肥胖反应中的有趣的品系差异一些会发展成全身性炎症，而另一些则不会这将帮助我们分离早期全身性炎症的具体机制。最后，重点放在 这是一种新兴的机制，作为一个关键的共同原因，过度炎症的哮喘和肥胖，我们将研究发作性缺氧（EH）使用常压缺氧室。我们实验室最近发表的基于大鼠幼崽自然行为的新方法将用于增加生命早期的身体活动，并将在成年大鼠中评估其对炎症和肌肉的影响。肌肉大小、表型和功能变化之间的关系将用于解释炎症相关细胞和分子机制的改变。我们已经靶向了连接肌肉中生长和炎症的特定途径，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解释生命早期发生的生理扰动的长期影响的细胞记忆因子中起着重要作用。因此，我们将研究已知的肌肉相关microRNA（例如，miR-1和miR-133），并分析新生和青春期动物肌肉中与可能的靶基因（MHC、IGF-I、IGFBP、IGF受体）相关的染色质中的DNA甲基化和组蛋白修饰。为了进一步加强PPG的整合，我们将开始 探索运动和炎症对循环中性粒细胞和单核细胞与生长中的肌肉相互作用的影响。结合项目I和II，这些研究将有助于开发基于机制的运动用途，作为对无数慢性儿童疾病的预防或治疗。

PROJECT DESCRIPTION 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 eariy 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.