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：
9741452
负责人：
David Kovacevic
金额：
$ 16.41万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-15 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9741452
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 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 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 recruit 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.

本 NIAMS K08 提案旨在为有前途的临床医生科学家职业发展机会初级骨科肩外科医生，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住院医师实习期间接受过肩部动物实验研究培训。这指导和研究支持委员会已准备好为学习多学科提供严格的指导对候选人来说最关键的学科机制研究知识和技能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并有受保护的研究时间。肩袖疾病是一些最常见的肌肉骨骼疾病，但治疗方法还需要进一步改进。关于肩袖疾病的科学发现可应用于不同解剖位置的其他炎症、退行性或创伤性疾病。我们的研究项目被特意选择提供培训机会，从而产生具有临床影响的发现，从而满足最成功的 K08 奖要求的所有必要要素。肩关节是人体中活动度最大的关节，由肩袖控制，肩袖由来自肩胛骨的肌腱组成肩胛骨并插入肱骨顶端的紧密区域。结果，肩袖很脆弱导致肌腱磨损和滑囊发炎，导致肩部疼痛和功能障碍。我们的长期科学目标是建立治疗肩袖的分子治疗方法失调。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。我们的初步数据表明，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。最有之一显着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 CXCR4/7（SDF-1 的特异性受体）的炎症细胞。我们建立了老鼠旋转器模拟人体肩袖炎症的袖带撕裂模型。我们的中心假设是 SDF-1/CXCR4/7 靶向减轻肩袖炎症并促进肩部周围肌腱修复的愈合联合的。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 是否介导炎症细胞的募集、细胞因子表达和体外肌腱-法氏囊细胞相互作用部位的 M1/M2 巨噬细胞极化。 (2)判断是否 SDF-1/CXCR4/7 靶向可减少炎症并增强体内肩袖肌腱撕裂的修复。我们的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范式通过局部递送靶向 SDF-1 或其他关键炎症介质来治疗肩部疾病抑制剂。拟议的研究应提供创新机制研究方面的严格培训，可以从而促进科学独立性的发展。