Therapeutic Strategies to Augment Muscle Rehabilitation

该项目的长期目标是开发新的治疗策略，改善肌肉萎缩， 加速脊髓损伤等病理条件下的肌肉康复。本申请是 符合克里斯托弗和达纳里夫瘫痪法案（CDRPA）的愿景，该法案促进了 开展类似工作的科学家之间的互动，以进一步增进了解， 为数百万瘫痪的美国人提供有效的治疗干预。“CDRPA鼓励 协调研究，以防止冗余，并希望加快发现更好的治疗方法， 第1页 治疗，同样重要的是，改善瘫痪患者今天的日常生活”。拟议 应用程序呈现了一组富有成效的科学家之间的独特合作， 互补的专业知识和对肌肉和运动功能恢复的共同兴趣。这队 国家专家探索了一个新的研究领域，重点是利用 调节肌肉生长的药理学/分子疗法与新兴康复结合 干预措施。 这项为期2年的申请的具体目标是：1）确定新的药理学策略， 改善废用/去负荷引起的肌肉萎缩，促进肌肉恢复; 2）验证一种新的 脊髓不完全损伤动物模型的康复策略的评估。该项目将 在快速药理学开发领域提供重要的临床前数据，并将为 更临床相关的脊髓损伤模型。靶向药物要么被批准用于人类， 使用或它们在临床开发中，并将允许快速转化为动物模型。该提案规定， 一些独特的机会，并提出了一个重要的一步，在翻译向人体试验。的 个别研究的结果也将为肌肉的科学基础做出重要的新贡献。 康复和脊髓损伤。这一协同方案的目标将在 以下三个项目： 项目I：减弱骨骼肌萎缩和肌肉功能丧失。 该项目将评估现有的药物，治疗目标是改善肌肉萎缩引起的 停用/卸载。具体而言，本项目将评估抑制蛋白水解在预防 的肌肉萎缩，并确定其对肌肉生长的影响后重新加载（与项目2和 芯A、B和C）。PI：H. Lee Sweeney - [目标1的范围已经缩小，目标2已经 删除]。 项目二：胰岛素样生长因子-I促进肌肉再生和康复。 该项目将研究胰岛素样生长因子I（IGF-I）的全身和局部递送的潜力， 促进后肢悬吊和石膏固定后废用/卸载后的肌肉再生和肥大 固定化（与项目1以及核心A、B和C合作）。PI：Elisabeth巴顿- [目标1和2是 已删除，目标3已删除]。 项目三：运动训练促进脊髓损伤后的肌肉康复。 本项目将验证一种新的不完全SCI动物模型，以促进未来针对 制定更有效的康复战略。可靠的SCI动物模型的可用性， 更接近地模拟临床情况将在SCI研究领域呈现显著的进步。 随后，本项目将评估实施活动康复的可行性和有效性 干预，如运动跑步机训练，在这个新的动物模型。[Aims 2-4已删除 和目标1已扩大到包括验证一个新的SCI模型之前，评估的影响， 跑步机运动训练干预]。 为了优化计划的经济性，三个集中的核心将继续支持所有三个项目。 核心将包括行政和数据管理核心（A）、脊髓损伤和 生理评估核心（B）和磁共振成像核心（C）。该计划是分布式的 横跨两个站点：佛罗里达大学和宾夕法尼亚大学。该计划建立在 两个工厂都拥有独特的互补专业知识和长期的富有成效的合作历史。

The long-range of this project is to develop novel therapeutic strategies that ameliorate muscle atrophy and accelerate muscle rehabilitation following pathological conditions such as spinal cord injury. This application is consistent with the vision of the Christopher and Dana Reeve Paralysis Act (CDRPA) which promotes the interaction of scientists conducting similar work to further enhance understanding and expedite the search for effective treatment interventions for millions of Americans living with paralysis. “The CDRPA encourages coordination of research to prevent redundancies and hopefully hasten discovery of better treatments and Page 1 cures and, as importantly, to improve the daily lives today for those living with paralysis”. The proposed application presents a unique collaboration between a group of productive scientists with diverse, yet complimentary expertise and a common interest in the recovery of muscle and motor function. This team of national experts explores a new area of research focusing on complimentary treatment strategies utilizing pharmacological/molecular therapies modulating muscle growth in conjunction with emerging rehabilitation interventions. The specific objectives of this 2 year application are: 1) To identify novel pharmacological strategies to ameliorate muscle atrophy induced by disuse/unloading and promote muscle recovery; 2) To validate a new animal model of incomplete spinal cord injury for the assessment of rehabilitation strategies. This Project will provide important preclinical data in an area of rapid pharmacological development and will set the stage for a more clinical relevant model of spinal cord injury. The drugs that are targeted are either approved for human use or they are in clinical development and will allow rapid translation to animal models. This proposal provides some unique opportunities and presents an important step forward in the translation towards human trials. The results of the individual studies will also make important new contributions to the science base of muscle rehabilitation and spinal cord injury. The objectives of this synergistic program will be addressed in the following three projects: Project I: Attenuation of Skeletal Muscle Atrophy and Loss of Muscle Function. This project will evaluate existing drugs, with the therapeutic goal of ameliorating muscle atrophy induced by disuse/unloading. Specifically, this project will assess the efficacy of inhibition of proteolysis in the prevention of muscle atrophy and determine its impact on muscle growth upon reloading (collaboration with Project 2 and Cores A, B and C). PI: H. Lee Sweeney – [The scope of Aim 1 had been reduced and Aim 2 has been removed]. Project II: Promoting Muscle Regeneration and Rehabilitation by Insulin-like Growth Factor-I. This project will investigate the potential of systemic and local dellivery of insulin-like growth factor I (IGF-I) to promote muscle regeneration and hypertrophy following disuse/unloading after hindlimb suspension and cast immobilization (collaboration with Project 1, and Cores A, B, and C). PI: Elisabeth Barton – [Aims 1 & 2 are reduced and Aim 3 has been removed]. Project III: Locomotor Training to Promote Muscle Rehabilitation following Spinal Cord Injury. This project will validate a new animal model of incomplete SCI to faciliate future studies targeting the development of more effective rehabilitation strategies. The availability of a reliable SCI animal model that more closely mimics the clinical situation would present a significant advance in the field of SCI research. Subsequently, this project will evaluate the feasibility and efficacy of implementing activity based rehabilitation interventions, such as locomotor treadmill training, in this new animal model. [Aims 2-4 have been removed and Aim 1 has been expanded to include validation of a new SCI model before evaluating the effect of the treadmill locomotor training intervention]. To optimize the economy of the program three centralized cores will continue to support all three projects. The cores will consist of an Administrative and Data Management Core (A), a Spinal Cord Injury and Physiological Assessment Core (B), and a Magnetic Resonance Imaging Core (C). The program is distributed across the two sites: the University of Florida and the University of Pennsylvania. The program builds on the unique, complementary expertise at both sites and a long history of productive collaboration.