MUSCLE RESPONSE TO STRESS IN CANINE MUSCULAR DYSTROPHY

该项目将为申请者提供研究技能 需要开发和评估康复治疗，以增强 肌肉营养不良患者的功能。在整个博士阶段 在生理学课程中，主要的努力将致力于 一个有指导的研究项目，它将考察 同种犬的机械应力和肌纤维损伤 杜兴氏肌营养不良症。这项研究的中心假设是 肌营养不良蛋白缺乏症肌肉纤维损伤的部分原因是 对过程中产生的机械应力的夸大反应 收缩。此外，肌肉与延长宫缩有关 比其他肌肉承受更大的压力，并且优先 受伤了。中心假说将在选定的后肢中进行检验 营养不良犬肌肉的细胞和生理学评价 肌肉纤维对不同水平的外加压力的反应特征。 尽管MDX鼠标更容易获得，而且更常见 使用实验模型，营养不良犬表现出临床特征 类似于患有杜氏肌营养不良症的人类。目标1将 肌膜损伤与肌纤维坏死的相关性：AIM 2将 比较与延长有关的肌肉的再生特征 肌肉参与缩短收缩的收缩：目标3 将确定是否存在较低的应激诱导损伤阈值 营养不良纤维与对照组的比较：Aim 4将确定 在生长过程中减少机械应力将消除或减少 成人中可见夸大的纤维坏死和重塑 腓肠肌。预计调查结果将改善 了解营养不良肌肉对身体应激的反应 从而改善了Duchenne肌肉症患者的治疗 营养不良。

This project will provide the applicant with the research skills required to develop and assess rehabilitation treatments that enhance function for patients with muscular dystrophy. Throughout a doctoral program in physiology, a major portion of effort will be devoted to a mentored research project which will examine the relationship between mechanical stress and muscle fiber injury in a canine homolog of Duchenne muscular dystrophy. The central hypothesis of this research is that fiber damage in dystrophin-deficient muscle results, in part, from an exaggerated response to mechanical stress incurred during contraction. Furthermore, muscles involved in lengthening contractions are subject to greater stress than other muscles, and are preferentially injured. The central hypothesis will be tested in selected hindlimb muscles of dystrophic dogs by evaluating cellular and physiological features of muscle fiber response to varying levels of imposed stress. Although the mdx mouse is more readily available and a more commonly used experimental model, the dystrophic dog expresses clinical features analogous to humans with Duchenne muscular dystrophy. Aim 1 will correlate muscle membrane damage with myofiber necrosis: Aim 2 will compare regenerative features in muscles involved in lengthening contractions with muscles involved in shortening contractions: Aim 3 will determine if a lower threshold to stress-induced injury exists in dystrophic fibers compared to controls: and Aim 4 will determine if reducing mechanical stress during growth will eliminate or decrease the exaggerated fiber necrosis and remodeling seen in the adult gastrocnemius muscle. It is anticipated that findings will improve the understanding of how dystrophic muscle responds to physical stress resulting in improved treatment for patients with Duchenne muscular dystrophy.