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：
8532820
负责人：
Brian Feeley
金额：
$ 7.34万
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/8532820
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.

描述（由申请人提供）：肩袖撕裂（RCT）是肩部疼痛和残疾的极其常见的原因。高达 20% 的 50 岁以上患者有肩袖撕裂的证据。此外，无症状袖带撕裂的患者往往会发展为较大的、有症状的撕裂。小型随机对照试验的手术修复效果良好，但大型随机对照试验的手术治疗取得的成功有限。大量随机对照试验已被发现与肩袖肌肉萎缩有关。此外，大量 RCT 与脂肪浸润的发展有关，这种现象似乎是人类肩袖所特有的现象。重要的是，具有萎缩和脂肪浸润的大型 RCT 患者的临床结果比没有萎缩和脂肪浸润的患者更差。因此，肩袖大撕裂的自然病程似乎是肌肉萎缩和脂肪浸润的发展，这会导致患者预后不佳。导致肩袖肌肉萎缩和脂肪浸润发生的分子机制尚未明确。本研究的目的是评估对动物模型中萎缩和脂肪浸润的发展至关重要的特定途径的作用肩袖撕裂。我们将建立对肌肉萎缩和脂肪浸润的发展至关重要的可能途径。我们随后将确定如何通过肌肉去神经支配来修改这些通路，因为此功能可能是相关通路的关键修饰符。我们将重点关注在其他模型中发现的调节肌肉萎缩和脂肪相关基因表达的关键途径。具体来说，我们将评估 Akt/mTOR 通路与肌肉萎缩的关系，以及 PPARy-gamma 通路与脂肪浸润的关系。了解这些机制可能有助于制定治疗方式，从而抑制甚至逆转大规模随机对照试验修复后的脂肪浸润和萎缩过程。