Physical activity profoundly influences health in children ranging from diseases like asthma to lifelong conditions like obesity, metabolic syndrome, and cardiovascular disease. The mechanisms of these effects remain largely elusive, but the recent demonstration that exercise robustly alters leukocytes and the mediators they produce in healthy children, and that many of the same cells and mediators are involved in asthma and the metabolic syndrome have opened new areas of investigation. This research is designed to examine molecular mechanisms that regulate the effect of exercise on both growth and inflammatory mediators [including growth hormone, interleukin-6 (IL-6), insulin-like growth factor-l, tumor necrosis factor-a (TNF-a)] produced by peripheral blood mononuclear cells (PBMCs) in healthy children. Collectively, these cells, cytokines, and growth factors are emerging as a pivotal interface between physical activity, growth, and disease pathogenesis in children. The following hypotheses will be tested: 1) Brief bouts of exercise in children produce a simultaneous, seemingly paradoxical stimulation of both pro-and anti-inflammatory (catabolic and anabolic) intracellular PBMC cytokines, chemokines, and growth factors;2) The balance of the PBMC genomic and mediator responses to exercise in children and adolescents is influenced by gender, pubertal status, body composition, and fitness;and 3) Even in healthy children, the balance of the PBMC responses to exercise will correlate with surrogate markers of disease risk associated with asthma [e.g., T-Helper cell typel and 2 balance (TH1/TH2)] and the metabolic syndrome (e.g., PBMC production of TNF-a). The study is focused on pre- and late pubertal, males and females, and 2 phases of this research are envisioned. In Phase 1, the genomic responses to brief exercise in PBMCs will be determined. Flow cytometry and intracellular permeability studies will then be done to determine which key cytokines and growth factors within the PBMCs are altered by exercise. In Phase 2, PBMCs obtained from children during exercise will be isolated and sorted and their ability to produce specific mediators will be measured intracellularly and by RT-PCR analysis of key regulatory genes. Specific inhibitors and blocking antibodies will be used to determine which of the potential circulatory factors (e.g., GH, IL-6) stimulated by exercise modulate intracellular production of cell cytokines, chemokines, or growth factors in children. PBMC responses to exercise will be correlated with gender, maturational status, body composition (measured by DEXA), fitness (measured by cycle ergometry), TH1fi~H2 status, and biochemical precursors of the metabolic syndrome (glucose, insulin, lipids). This research will contribute to the development of exercise guidelines for healthy children, as well as for children with chronic disease and disability in whom physical activity is beneficial, but only if the dose does not exacerbate underlying inflammatory, metabolic, or physiological abnormalities.
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