Molecular pathophysiology of massive rotator cuff tears

大量肩袖撕裂的分子病理生理学

基本信息

批准号：
8288666
负责人：
Brian Feeley
金额：
$ 7.73万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-17 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8288666
关键词：
Activities of Daily Living Affect Age Age-Years Animal Model Animals Atrophic Characteristics Chronic Clinical Critical Pathways Degradation Pathway Denervation Development Evaluation Family member Fatty acid glycerol esters Functional disorder Gene Family Genes Healed Homologous Gene Human Individual Infiltration Injury Lead Mechanics Modality Modeling Molecular Muscle Muscle denervation procedure Muscular Atrophy Natural History Nerve Operative Surgical Procedures Orthopedics Outcome Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Peroxisome Proliferators Physicians Population Process Protein Biosynthesis Proteins Rattus Receptor Activation Regulation Regulatory Pathway Role Rotator Cuff Rupture Shoulder Shoulder Pain Signal Pathway Tendon Injuries Tendon structure Testing Therapeutic Time achilles tendon aging population arm clinically relevant disability functional outcomes healing improved inhibitor/antagonist injured interest mTOR protein multicatalytic endopeptidase complex nerve injury novel quadriceps muscle repaired success

项目摘要

DESCRIPTION (provided by applicant): Rotator cuff tears (RCTs) are an extremely common cause of shoulder pain and disability. Up to 20% of patients greater than the age of 50 years of age have evidence of a rotator cuff tear. In addition, patients with asymptomatic cuff tears tend to progress to larger, symptomatic tears. The outcomes of surgical repair of small RCT are good, but there has been limited success in the surgical treatment of massive RCTs. Massive RCT have been found to be associated with atrophy of the rotator cuff muscles. In addition, massive RCT are associated with the development of fatty infiltration, a phenomenon that appears to be unique to the rotator cuff in humans. Importantly, patients with large RCT with atrophy and fatty infiltration have poorer clinical outcomes than those that do not have atrophy and fatty infiltration. Thus, it appears that the natural history of large rotator cuff tears is th development of muscle atrophy and fatty infiltration, which leads to poor patient outcomes. The molecular mechanisms that lead to the development of rotator cuff muscle atrophy and fatty infiltration have not been defined. The purpose of this study is to evaluate the role of specific pathways that are critical for the development of atrophy and fatty infiltration in an animal model of rotator cuff tears. We will establish the likely pathways critical to the development of muscle atrophy and fatty infiltration. We will subsequently determine how these pathways are modified by muscle denervation, since this feature is likely a key modifier of the relevant pathways. We will focus on key pathways that have been found in other models to regulate muscle atrophy and expression of fat related genes. Specifically, we will evaluate the Akt/mTOR pathway as it relates to muscle atrophy, and the PPARy-gamma pathways are they relate to fatty infiltration. Understanding these mechanisms may allow for therapeutic modalities that would allow for inhibition or even reversal of the fatty infiltration and atrophic process following repair of massve RCTs. PUBLIC HEALTH RELEVANCE: Rotator cuff tears are one of the most common orthopaedic conditions, affecting up to 20% of patients greater than 50 years of age. Large rotator cuff tears do not heal, result in poor shoulder function, and lead to irreversible muscle changes. The purpose of this study is to understand the expression of specific proteins that lead to the irreversible muscle changes found in the setting of large rotator cuff tears.

描述（由申请人提供）：肩袖撕裂（RCT）是肩部疼痛和残疾的极为普遍原因。大于50岁大的患者中，多达20％的患者有肩袖撕裂的证据。此外，无症状袖口泪水的患者倾向于发展到更大的有症状的眼泪。小RCT手术修复的结果很好，但是在大规模RCT的手术治疗方面取得了有限的成功。已经发现大量RCT与肩袖肌肉的萎缩有关。此外，大规模的RCT与脂肪浸润的发展有关，脂肪浸润的发展似乎是人类肩袖的独特现象。重要的是，与没有萎缩和脂肪浸润的患者相比，患有萎缩和脂肪浸润的大RCT患者的临床结局较差。因此，似乎大肩袖撕裂的自然历史是肌肉萎缩和脂肪浸润的发展，这导致患者的结局差。尚未定义导致肩袖肌肉萎缩和脂肪浸润的分子机制。这项研究的目的是评估特定途径的作用，这对于动物模型中萎缩和脂肪浸润至关重要肩袖的眼泪。我们将建立可能对肌肉萎缩和脂肪浸润的发展至关重要的途径。随后，我们将确定这些途径如何通过肌肉去神经修饰，因为此功能可能是相关途径的关键修饰符。我们将重点关注其他模型中发现的关键途径，以调节肌肉萎缩和脂肪相关基因的表达。具体而言，我们将评估与肌肉萎缩有关的AKT/MTOR途径，并且PPARY-GAMMA途径与脂肪浸润有关。理解这些机制可能会允许治疗方式，从而可以抑制甚至逆转大量RCT后脂肪浸润和萎缩过程。公共卫生相关性：肩袖撕裂是最常见的骨科状况之一，影响了50岁以上的患者中有20％。大肩袖撕裂不会愈合，导致肩部功能不佳，并导致不可逆转的肌肉改变。这项研究的目的是了解特定蛋白质的表达，这些蛋白质会导致在大肩袖撕裂的情况下发现不可逆的肌肉变化。