Molecular pathophysiology of massive rotator cuff tears

描述(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。高达20%的大于50岁的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进展为更大的有症状的撕裂。小RCT的手术修复效果良好，但在巨大RCT的手术治疗中取得的成功有限。大量的RCT被发现与肩袖肌肉的萎缩有关。此外，大量的RCT与脂肪渗透的发展有关，这种现象似乎是人类肩袖独有的。重要的是，伴有萎缩和脂肪渗透的大RCT患者的临床结果比那些没有萎缩和脂肪渗透的患者更差。因此，大型肩袖撕裂的自然病史是肌肉萎缩和脂肪渗透，这会导致不良的患者预后。导致肩袖肌肉萎缩和脂肪渗透的分子机制尚未明确。这项研究的目的是评估在动物模型中发生萎缩和脂肪渗透的关键特定途径的作用。 肩袖撕裂。我们将建立对肌肉萎缩和脂肪渗透的发展至关重要的可能途径。我们随后将确定肌肉失神经是如何改变这些通路的，因为这一特征可能是相关通路的关键修饰物。我们将重点介绍在其他模型中已发现的调节肌肉萎缩和脂肪相关基因表达的关键途径。具体地说，我们将评估Akt/mTOR通路与肌肉萎缩有关，以及PPARy-Gamma通路与脂肪渗透有关。了解这些机制可能有助于治疗方法，从而抑制甚至逆转修复大量RCT后的脂肪渗透和萎缩过程。

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.