Assess Anabolic Agents/Exercise in Burned Children

描述（申请人提供）：该申请是一种竞争性更新，其最初假设对大于40%总体表面积烧伤的热损伤的高代谢反应持续了烧伤后的整个第一年，并且部分由皮质醇和儿茶酚胺产生的增加介导，导致肌肉消耗、虚弱、免疫抑制、慢性骨丢失、生长减缓，以及代谢、血液动力学、炎症和瘢痕反应的增加。 我们已经证明，对严重烧伤的高代谢反应与静息能量消耗增加、胰岛素抵抗、免疫缺陷， 以及受伤后持续数月的全身痉挛。 此外，严重烧伤后6个月和9个月，骨矿物质含量、瘦体重和肌肉力量下降。 我们还表明，这些反应可以受到高碳水化合物饮食，运动和生长激素的积极影响。 运动的强大好处使我们提出了三个研究项目和三个核心单元。 项目1将检验以下假设：饮食和运动与普萘洛尔、氧雄龙或皮质醇阻滞剂（酮康唑）的每日给药相结合，将改善烧伤儿童的临床结局并促进功能恢复。 项目2，检验糖皮质激素拮抗作用是烧伤儿童肌肉恢复不可或缺的假设。 项目3，将检验以下假设：肝和肌肉中细胞内甘油三酯的积累直接导致这些组织中的胰岛素抵抗，或表明活性脂肪酸产物的细胞内积累，从而破坏胰岛素作用。 这些项目，分析核心，质谱核心和人类受试者核心，使我们能够研究运动和合成代谢/抗分解代谢药物影响肌肉蛋白质代谢（项目2），脂肪代谢及其与肌肉和肝脏中蛋白质代谢的相互作用（项目3）的机制，以及这些机制如何转化为临床结果和烧伤儿童的康复（项目1）。

DESCRIPTION (provided by applicant): This application is a competitive renewal which originally hypothesized that hypermetabolic responses to a thermal injury greater than 40% total body surface area burned, persisted throughout the first year post burn, and was partially mediated by an increase in the production of cortisol and catecholamines leading to muscle wasting, weakness, immunosuppression, chronic bone loss, decreased growth, and increases in metabolic, hemodynamic, inflammatory and scar responses. We have shown that the hypermetabolic response to a severe burn is associated with increased resting energy expenditure, insulin resistance, immunodeficiency, and whole body catabolism that persists for months after injury. Furthermore, bone mineral content, lean body mass, and muscle strength is decreased at 6 and 9 months after severe burn. We have also shown that these responses can be positively affected by a high carbohydrate diet, exercise and growth hormone. The strong benefits of exercise have led us to propose three research projects and three core units. Project 1 will test the hypothesis that diet and exercise in conjunction with daily administration of propranolol, oxandrolone, or a cortisol-blocking agent (ketoconazole) will improve clinical outcomes and promote functional recovery in burned children. Project 2, tests the hypothesis that glucocorticoid antagonism is integral to the restoration of muscle anabolism in burned children. Project 3, will test the hypothesis that accumulation of intracellular triglycerides in liver and muscle directly causes insulin resistance in those tissues, or indicates intracellular accumulation of active fatty acid products, thereby disrupting insulin action. These projects, the Analytic Core, the Mass Spectrometry Core, and the Human Subjects Core, allow us to study mechanisms by which exercise and anabolic/anticatabolic agents affect muscle protein metabolism (Project 2), fat metabolism, and its interaction with protein metabolism in muscle and liver (Project 3), and how these mechanisms translate to clinical outcomes and the rehabilitation of burned children (Project 1).