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Inflammation in Rotator Cuff Tear and Repair

肩袖撕裂和修复中的炎症

基本信息

批准号：
9370648
负责人：
David Kovacevic
金额：
$ 16.41万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9370648
关键词：
Anatomy Animal Experimentation Animal Experiments Award Bioethics Biology Biometry CXCR4 Receptors CXCR4 gene Cell Communication Cells Chairperson Clinical Collaborations Data Department chair Development Disease Doctor of Medicine Education Educational workshop Elements Employee Strikes Experimental Designs Fellowship Functional disorder Funding Goals Grant Healthcare Systems Human Human body In Vitro Inflammation Inflammation Mediators Inflammatory Joint structure of shoulder region Joints Knowledge Lead Learning Location Mediating Medical Education Mentors Mentorship Modeling Molecular Musculoskeletal Musculoskeletal Diseases Musculoskeletal System National Institute of Arthritis and Musculoskeletal and Skin Diseases ORALIT Operative Surgical Procedures Orthopedic Surgery procedures Orthopedics Paper Publications Rattus Recording of previous events Recruitment Activity Rehabilitation therapy Research Research Methodology Research Personnel Research Project Grants Research Support Research Training Residencies Rotator Cuff Science Scientist Series Shoulder Shoulder Pain Site Special Hospitals Stromal Cell-Derived Factor 1 Surgeon Talents Tendon structure Therapeutic Time Tissues Training United States National Institutes of Health Universities Work career development chemokine clinically relevant cytokine experimental study faculty mentor healing humerus in vivo independency infrastructure development inhibitor/antagonist injury and repair innovation macrophage medical schools meetings member multidisciplinary novel therapeutics precision medicine professor reconstruction repaired responsible research conduct rotator cuff injury rotator cuff tear scapula skills training opportunity

项目摘要

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.

NIAMS K08提案旨在为有前途的医生-科学家职业发展提供机会初级整形外科肩部外科医生，具有重建肩部手术的临床专业知识。候选人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。这个指导和研究支持委员会准备为学习多学科提供严格的指导纪律机制研究知识和技能，这对候选人的发展成为一名独立的骨科外科科学家。候选人有强有力的机构支持。拥有受保护的研究时间。肩袖疾病是最常见的肌肉骨骼疾病之一，然而，治疗方法还需要进一步改进。有关肩袖疾患的科学发现可应用于不同解剖位置的其他炎症性、退行性或创伤性疾病。我们的研究项目被故意选择来提供培训机会，这些培训机会将导致临床上有影响的发现，从而满足最成功的K08奖项要求的所有必要要素。肩关节是关节人体内最活跃的关节，由一个由肌腱组成的肩袖控制，这些肌腱从肩胛骨，并插入在肱骨顶端的一个紧凑区域。因此，肩袖是脆弱的。肌腱磨损和法氏囊发炎，导致肩部疼痛和功能障碍。我们的长期的科学目标是建立一种治疗肩袖的分子治疗方法精神错乱。然后我们可以将这种治疗方法应用于治疗其他炎症性疾病肌肉骨骼系统。我们的初步数据显示，发炎的人体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。其中最主要的炎症介质是基质细胞衍生因子-1(SDF-1)，它是一种趋化因子，负责动员携带SDF-1特异性受体CXCR4/7的炎症细胞。我们已经建立了老鼠轮转器模拟人体肩袖发炎的袖口撕裂模型。我们的中心假设是SDF-1/CXCR4/7 靶向减轻肩袖炎症，促进肩部肌腱修复愈合联合。我们将进行严格的科学实验，以实现以下两个具体目标。(1)至确定SDF-1/CXCR4/7是否介导炎性细胞的募集、细胞因子的表达以及肌腱-法氏囊细胞相互作用部位的M1/M2巨噬细胞极化。(2)确定是否 SDF-1/CXCR4/7靶向治疗可减轻炎症并促进体内撕裂的肩袖肌腱的修复。我们的提案在精密医学时代是有影响力的，因为我们正在引入一种新的治疗范式通过靶向SDF-1或其他关键的炎症介质局部注射治疗肩部疾病抑制剂。拟议的研究应在创新的机械研究方面提供严格的培训，导致科学自主性的发展。