Inflammation in Rotator Cuff Tear and Repair

该NIAMS K08提案旨在为有前途的临床医生-科学家提供职业发展机会。 具有肩关节重建手术临床专业知识的初级肩关节矫形外科医生。候选 在医学院教育和实习期间接受过肩部动物实验的研究培训。的 指导和研究支持委员会随时准备为学习多方面提供严格的指导， 学科机械研究知识和技能，这将是最关键的候选人的 发展成为一名独立的骨科医生科学家。候选人拥有强大的机构支持 受保护的研究时间。肩袖疾病是一些最常见的肌肉骨骼疾病， 但治疗方法仍需进一步改进。关于肩袖疾病的科学发现可以应用于 不同解剖位置的其他炎性、退行性或创伤性疾病。我们的研究项目 是特意选择提供培训机会，将导致临床上有影响力的发现， 从而满足最成功的K08奖项要求的所有必要元素。肩关节 人体中最移动的关节，由肌腱组成的肩袖操纵，肌腱来自 肩胛骨和插入在一个紧张的地区顶端肱骨。因此，肩袖是脆弱的 肌腱的磨损和囊的炎症，导致肩部疼痛和功能障碍。我们 长期的科学目标是建立一种分子治疗方法来治疗肩袖 紊乱然后，我们可以应用这种治疗方法来治疗其他炎症性疾病， 肌肉骨骼系统我们的初步数据显示，发炎的人类肩袖组织和细胞 与正常肩袖组织相比，表达更高水平的细胞因子和趋化因子。一个最 显著的炎性介质是基质细胞衍生因子-1（SDF-1），其是负责 动员携带CXCR4/7的炎性细胞，CXCR4/7是SDF-1的特异性受体。我们已经建立了大鼠旋转器 模拟人类肩袖炎症的肩袖撕裂模型。我们的中心假设是SDF-1/CXCR4/7 靶向治疗可减轻肩袖炎症并促进肩关节周围肌腱修复的愈合 关节我们将进行严格的科学实验，以实现以下两个具体目标。(1)到 确定SDF-1/CXCR4/7是否介导炎性细胞的募集、细胞因子表达，以及 体外肌腱-囊细胞相互作用部位的M1/M2巨噬细胞极化。(2)以确定是否 SDF-1/CXCR4/7靶向减少炎症并增强体内撕裂的肩袖肌腱的修复。我们 该提案在精准医学时代具有影响力，因为我们正在引入一种新的治疗模式 通过靶向SDF-1或其他关键炎症介质， 抑制剂的拟议的研究应提供严格的培训，在创新的机制研究， 引导科学自主性的发展。

This NIAMS K08 Proposal seeks to provide a clinician-scientist career development opportunity for a promising junior orthopaedic shoulder surgeon with clinical expertise in reconstructive shoulder surgeries. The candidate had research training in shoulder animal experiments during medical school education and residency. The Mentoring and Research Support Committee is ready to provide rigorous guidance for learning multi- disciplinary mechanistic research knowledge and skills that will be most critical for the candidate's development into an independent orthopaedic surgeon scientist. The candidate has strong institutional support with protected research time. Rotator cuff disorders are some of the most common musculoskeletal disorders, yet treatments need further improvement. Scientific discoveries about rotator cuff disorders can be applied to other inflammatory, degenerative, or traumatic disorders in different anatomic locations. Our research project was deliberately chosen to provide training opportunities that will lead to clinically impactful discoveries, thereby fulfilling all necessary elements of the most successful K08 Award requirements. The shoulder joint is the most mobile joint in the human body, steered by a rotator cuff consisting of tendons arising from the scapula and inserting in a tight region on the top end of the humerus. As a result, the rotator cuff is vulnerable to wear-and-tear of the tendons and inflammation of the bursa, resulting in shoulder pain and dysfunction. Our long-range scientific goal is to establish a molecular therapeutic approach for the treatment of rotator cuff disorders. We can then apply this therapeutic approach to treat other inflammatory disorders in the musculoskeletal system. Our Preliminary Data showed that inflamed human rotator cuff tissues and cells express higher levels of cytokines and chemokines compared to normal rotator cuff tissues. One of the most striking inflammatory mediators is stromal cell derived factor-1 (SDF-1), which is a chemokine responsible for mobilizing inflammatory cells bearing CXCR4/7, a specific receptor for SDF-1. We have established rat rotator cuff tear models that simulate human rotator cuff inflammation. Our central hypothesis is that SDF-1/CXCR4/7 targeting mitigates rotator cuff inflammation and promotes healing of the tendon repair around the shoulder joint. We will conduct rigorous scientific experiments to accomplish the following two Specific Aims. (1) To determine whether SDF-1/CXCR4/7 mediates recruitment of inflammatory cells, cytokine expression, and M1/M2 macrophage polarization at the site of tendon-bursal cell interactions in vitro. (2) To determine whether SDF-1/CXCR4/7 targeting reduces inflammation and enhances repair of torn rotator cuff tendons in vivo. Our proposal is impactful in the era of Precision Medicine because we are introducing a new therapeutic paradigm for shoulder disorders by targeting SDF-1 or other key mediators of inflammation with locally delivered inhibitors. The proposed study should provide rigorous training in innovative mechanistic research that can lead to the development of scientific independency.