Mechanisms and therapies for respiratory muscle failure

描述（由申请方提供）：本申请拟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性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是必不可少的，并且编码肌营养不良蛋白及其相关蛋白的基因中的突变是肌营养不良症的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岁之前丧失，需要肺支持。呼吸功能障碍在肌营养不良症是临床上重要的，并在很大程度上研究不足。本研究旨在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和治疗益处的机制。已经在缺乏抗肌萎缩蛋白相关蛋白3-肌聚糖（Sgcg null）的小鼠中进行了初步研究，因为这些小鼠显示出严重的表型，与人类患者中观察到的最相似。在该模型中，膈肌严重病变。我们先前描述了Sgcg敲除小鼠在置于129 Sv/J背景下时显示出不太严重或受保护的表型。这些小鼠被命名为“129-Sgcg”。当在DBA 2 J背景（D2-Sgcg）中时，Sgcg无效等位基因具有更严重或增强的表型。D2-Sgcg小鼠品系具有过度活化的TGF 2信号级联，导致在这些小鼠中观察到的纤维化增加。膈肌纤维化作为一种数量性状的基因组定位已经产生了四个染色体基因座，其调节D2-Sgcg和129-Sgcg品系之间的F2动物队列中的膈肌纤维化。值得注意的是，这些遗传基因座在基于肢体的肌肉和膈肌之间是不同的，突出了呼吸系统的独特病理。我们还将Sgcg无效等位基因引入到“超级愈合”MRL背景中，并发现MRL贡献减少了膈肌和心肌中的疾病进展。我们假设，修饰基因调节纤维化差异膈肌相比，其他骨骼肌。我们还假设TGF-2介导的纤维化和由此产生的瘢痕组织在功能上阻碍了肌营养不良症和其他肺部疾病中的膈肌功能。

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.