Mechanisms and therapies for respiratory muscle failure

描述（由申请人提供）：本申请旨在研究与进行性肌肉退行性疾病相关的呼吸功能不全。肌肉退行性疾病的致死率是由呼吸和心脏功能障碍引起的。肌营养不良蛋白复合物对于提供骨骼肌纤维和心肌细胞的稳定性至关重要，而编码肌营养不良蛋白及其相关蛋白的基因突变是肌营养不良最常见和最严重的原因。在杜氏肌营养不良症中，呼吸肌功能在20岁时丧失，需要肺支持。肌营养不良患者的呼吸功能障碍在临床上很重要，但尚未得到充分的研究。我们建议探讨心肺功能障碍的病理机制及其对治疗的反应。此外，来自体外和体内技术的数据将被整合，以充分研究呼吸系统疾病进展的机制和治疗益处。在缺乏肌营养不良蛋白相关蛋白3-肌糖聚糖（Sgcg null）的小鼠中进行了初步研究，因为这些小鼠表现出严重的表型，与人类患者最相似。在这个模型中膈肌病变严重。我们之前描述过，当放置在129Sv/J背景中时，Sgcg缺失小鼠显示出较不严重或受保护的表型。这些小鼠被命名为“129-Sgcg”。Sgcg空等位基因在DBA2J背景下具有更严重或增强的表型（D2-Sgcg）。D2-Sgcg小鼠品系具有超激活的TGF2信号级联，导致在这些小鼠中观察到的纤维化加剧。横膈膜纤维化作为一种数量性状的基因组图谱已经在D2-Sgcg和129-Sgcg菌株之间的F2队列动物中发现了四个调节横膈膜纤维化的染色体位点。值得注意的是，这些基因位点在肢基肌和横膈膜肌之间是不同的，突出了呼吸系统的独特病理。我们还将Sgcg空等位基因引入“超愈合”MRL背景，发现MRL的作用可减少横膈膜和心肌的疾病进展。我们假设与其他骨骼肌相比，修饰基因对膈肌纤维化的调节存在差异。我们还假设tgf2介导的纤维化和由此产生的疤痕组织在功能上阻碍了肌营养不良和其他肺部疾病中的横膈肌功能。

DESCRIPTION (provided by applicant): This application proposes to study respiratory insufficiency associated with progressive muscle degenerative disorders. Lethality in muscle degenerative disorders arises from a combination respiratory and cardiac dysfunction. The dystrophin complex is essential for providing stability to skeletal myofibers and cardiomyocytes, and mutations in the genes encoding dystrophin and its associated proteins are the most common and most severe causes of muscular dystrophy. In Duchenne Muscular dystrophy, respiratory muscle function is lost by the age of 20 necessitating pulmonary support. Respiratory dysfunction in the muscular dystrophies is clinically important and largely understudied. We propose to investigate the pathological mechanisms of cardiopulmonary dysfunction and its response to therapy. Furthermore, data from in vitro and in vivo techniques will be integrated in order to fully investigate the mechanisms of respiratory disease progression and therapeutic benefits. Preliminary studies have been conducted in mice lacking the dystrophin-associated protein, 3-sarcoglycan (Sgcg null) since these mice display a severe phenotype, most similar to what is seen in human patients. The diaphragm muscle is severely diseased in this model. We previously described that Sgcg null mice display a less severe or protected phenotype when placed in the 129Sv/J background. These mice are designated "129-Sgcg". The Sgcg null allele has a more severe or enhanced phenotype when in the DBA2J background (D2-Sgcg). The D2-Sgcg mouse strain has a hyper- activated TGF2 signaling cascade leading to the heightened fibrosis observed in these mice. Genomic mapping of diaphragm fibrosis as a quantitative trait has yielded four chromosomal loci that modulate diaphragm fibrosis in an F2 cohort of animals between the D2-Sgcg and 129-Sgcg strains. Notably, these genetic loci are different between limb based muscle and the diaphragm muscle highlighting the unique pathology of the respiratory system. We also introduced the Sgcg null allele into the "super-healing" MRL background and find that the MRL contribution reduces disease progression in diaphragm and cardiac muscles. We hypothesize that modifier genes regulate fibrosis differentially in diaphragm muscle compared to other skeletal muscles. We also hypothesize that TGF2-mediated fibrosis and resultant scar tissue functionally impedes diaphragm muscle function in muscular dystrophy and other pulmonary diseases.