Therapeutic Strategies to Augment Muscle Rehabilitation

该项目的长远目标是开发新的治疗策略，以改善肌肉萎缩和 在脊髓损伤等病理情况下，加速肌肉康复。此应用程序是 符合克里斯托弗和达纳·里夫麻痹法案(CDRPA)的愿景，该法案促进 开展类似工作的科学家之间的互动，以进一步增进了解和加快搜索 对数百万瘫痪的美国人进行有效的治疗干预。“CDRPA鼓励 协调研究以防止冗余，并有望加速发现更好的治疗方法和 第1页 治疗，同样重要的是，改善当今瘫痪患者的日常生活“。建议数 应用程序呈现了一组富有成效的科学家之间的独特合作，这些科学家具有不同的 免费赠送的专业知识和对肌肉和运动功能恢复的共同兴趣。这支队伍 国家专家探索了一个新的研究领域，重点是利用免费治疗战略 结合新兴康复调整肌肉生长的药物/分子疗法 干预措施。 这项为期两年的申请的具体目标是：1)确定新的药理策略以 改善废用/卸载引起的肌肉萎缩，促进肌肉恢复；2)验证一种新的 不完全性脊髓损伤动物模型的康复策略评估。该项目将 在药理学快速发展的领域提供重要的临床前数据，并将为 更具临床相关性的脊髓损伤模型。这些靶向药物要么被批准用于人类 或者它们正在临床开发中，并将允许快速转化为动物模型。这份提案提供了 一些独特的机会，并在转化为人体试验方面向前迈出了重要的一步。这个 单项研究的结果也将为肌肉科学基础做出重要的新贡献 康复和脊髓损伤。这一协同计划的目标将在 以下是三个项目： 项目一：减轻骨骼肌萎缩和肌肉功能丧失。 这个项目将评估现有的药物，治疗目标是改善由 停用/卸载。具体地说，该项目将评估抑制蛋白质分解在预防 肌肉萎缩并确定其在重新负荷时对肌肉生长的影响(与项目2和 核心A、B和C)。PI：H.Lee Sweeney-[目标1的范围已经缩小，目标2的范围已经缩小 已删除]。 项目II：胰岛素样生长因子-I促进肌肉再生和康复。 该项目将研究全身和局部应用胰岛素样生长因子I(IGF-I)的潜力。 促进后肢悬吊石膏后废用/卸载后肌肉再生和肥大 固定(与项目1以及核心A、B和C合作)。PI：伊丽莎白·巴顿-[目标1和目标2是 减少，目标3已被删除]。 项目三：促进脊髓损伤后肌肉康复的运动训练。 该项目将验证一种新的不完全性脊髓损伤动物模型，以促进未来针对 制定更有效的康复战略。一种可靠的脊髓损伤动物模型的可用性 更接近于临床情况将是脊髓损伤研究领域的重大进步。 随后，本项目将评估实施活动基础康复的可行性和有效性 在这种新的动物模型中进行干预，如运动跑步机训练。[目标2-4已被删除 Aim 1已经扩展到包括在评估 跑步机运动训练干预]。 为了优化方案的经济性，三个集中核心将继续为所有三个项目提供支持。 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)。该程序是分布式的 在两个网站上：佛罗里达大学和宾夕法尼亚大学。该计划建立在 这两个站点的独特、互补的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.