Molecular pathophysiology of massive 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一种非常常见的原因。超过20%的50岁以上的患者有肩袖撕裂的证据。此外，无症状袖带撕裂的患者倾向于进展为更大的有症状的撕裂。小RCT的手术修复结局良好，但大规模RCT的手术治疗成功率有限。已发现大量RCT与肩袖肌肉萎缩相关。此外，大量RCT与脂肪浸润的发展相关，这是人类肩袖特有的现象。重要的是，有萎缩和脂肪浸润的大型RCT患者的临床结局比没有萎缩和脂肪浸润的患者差。因此，大肩袖撕裂的自然病程似乎是肌肉萎缩和脂肪浸润的发展，这导致患者结局较差。导致肩袖肌肉萎缩和脂肪浸润的分子机制尚未确定。本研究的目的是评估在动物模型中对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肌肉萎缩和脂肪浸润发展的可能关键途径。我们随后将确定这些途径是如何通过肌肉去神经支配进行修改的，因为这个功能可能是相关途径的关键修改器。我们将专注于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。具体而言，我们将评估Akt/mTOR途径，因为它与肌肉萎缩有关，以及PPARy-γ途径，因为它们与脂肪浸润有关。了解这些机制可能会允许治疗方式，将允许抑制甚至逆转的脂肪浸润和萎缩过程后修复massve RCT。

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.