Treatment of Rabbit Rotator Cuff Fatty Infiltration and Atrophy with Electric Stimulation and a PDGFRa inhibitor

背景：PI建议检验以下假设：抑制血小板衍生生长因子 受体α(PDGFRA)和直接、次最大电刺激(ES)协同预防脂肪 肌袖撕裂后，肌肉萎缩，功能得到改善。无法修复的大型旋转器 袖带撕裂伴肌肉FI是他退伍军人管理局实践中最常见的诊断之一。根据 退伍军人管理局外科质量改进计划，1万多名退伍军人肩袖 伤员在六年的时间里接受了肩袖修复。肩袖撕裂的外科修复 大体上是成功的，尽管再撕裂率为25%。我们提出了一种新的FI方法 预防，并将研究这如何影响肌肉功能。 脂肪渗透和萎缩导致肌腱再次撕裂和肌肉减少的不良结果 功能。目标：这项提案的总体目的是确定是否治疗 FI和萎缩改善了兔动物模型的结果，如：动物步态、肌肉功能和 肩袖愈合。 目标1：确定肩袖撕裂时抑制PDGFR和直接肌肉ES是否可以 通过预防FI和兔肩袖的萎缩来改善肌肉功能 撕裂模型。 目标2：确定PDGFR抑制和直接肌肉电刺激是否可以抑制/阻碍FI和 使用延迟修复模型改善功能，其中FI和萎缩已经被 已经成立了。 研究设计和方法：本研究将利用一只已建立并可复制的兔 AIMS 1和AIMS 2慢性肩袖撕裂和肌肉脂肪渗透的活体模型：研究结果 这两个目标的措施包括：活体收缩肌肉功能测试，兔子步态分析， 肌肉脂肪渗出的显微CT定量成像、组织分析用于纤维成脂 细胞和脂肪/纤维化的特殊组织学。具体目标2将利用这些相同的结果，以及 肌腱功能测试，以确定粘弹性特性。 临床关系：肩袖撕裂合并不可逆转的FI在退伍军人中很常见， 排除了成功的修复和结果。最终目标是找到新的干预措施， 改善接受肩袖修复的退伍军人的功能。 影响/意义：拟议的优秀奖将为未来的临床试验奠定基础 在接下来的十年里，通过测试联邦药品管理局批准的两种治疗方法的协同效应 关于萎缩性肩袖撕裂的治疗。这种转化性的临床前方法有可能 目的：减轻疼痛，提高退伍军人的独立功能和恢复体力工作的能力。 此外，它还将为申请人在从事职业生涯时提供宝贵的研究支持。 整形外科医生--退伍军人事务部马里兰州医疗保健系统的科学家。[公安部有一支三人的队伍 合作研究人员在肩袖成像、肩袖肌肉生理学和脂肪细胞方面经验丰富 编队。]

Background: The PI proposes to test the hypothesis that inhibition of platelet-derived growth factor receptor alpha (PDGFRa) and direct, submaximal electric stimulation (ES) synergistically prevents fatty infiltration (FI) and muscle atrophy, improving function after rotator cuff tear. A large irreparable rotator cuff tear with muscle FI is one of the most common diagnoses seen in his VA practice. According to the Veterans Administration Surgical Quality Improvement Program, over 10,000 Veterans with rotator cuff injuries underwent rotator cuff repairs over a six-year span. Surgical repair of a torn rotator cuff is generally successful, though with a re-tear rate of 25 percent. We propose a novel method of FI prevention and will study how this affects muscle function. Fatty infiltration and atrophy leads to poor outcomes from tendon re-tear and decreased muscle function. Objectives: The overall purpose of this proposal is to determine whether the treatment of FI and atrophy improves outcomes in a rabbit animal model such as: animal gait, muscle function, and rotator cuff healing.  Aim 1: Determine if PDGFR inhibition and direct muscle ES at the time of rotator cuff tear can improve muscle function by preventing FI and atrophy in an established rabbit rotator cuff tear model.  Aim 2: Determine if PDGFR inhibition and direct muscle ES can arrest/impede FI and improve function using a delayed repair model in which FI and atrophy have been established. Research Design and Methodology: This study will utilize an established and reproducible rabbit in vivo model of chronic rotator cuff tear and muscle fatty infiltration in Aims 1 and 2. Study outcome measures for both aims include: in vivo contractile muscle function testing, rabbit gait analysis, quantitative-based micro-CT imaging of muscle fatty infiltration, tissue analysis for fibro-adipogenic cells and fat/fibrosis specific histology. Specific Aim 2 will utilize these same outcomes, as well as tendon functional testing to determine viscoelastic properties. Clinical Relationships: Rotator cuff tear with irreversible FI is common in the Veteran population and precludes a successful repair and outcome. The ultimate goal is finding novel interventions that can improve function for Veterans undergoing rotator cuff repair. Impact/Significance: The proposed Merit Award will lay the groundwork for future clinical trials within the next ten years by testing two Federal Drug Agency approved treatments for their synergistic effects on the treatment of atrophic rotator cuff tears. This translational pre-clinical approach has the potential to: reduce pain and improve Veteran's ability to function independently and return to physical work. Furthermore, it will provide valuable research support for the applicant as he pursues a career as an orthopaedic surgeon-scientist at the VA Maryland Health Care System. [The PI has a team of three co-investigators experienced in rotator cuff imaging, rotator cuff muscle physiology and adipocyte formation.]