Restoration of muscle cell adhesion to treat cardiomyopathy in muscular dystrophy

项目摘要 Duchenne肌营养不良症(DMD)是最常见的营养不良症，由基因突变引起 Dystrophin基因，导致dystrophin蛋白和整个dystrophin-糖蛋白复合体的丢失，这 保护肌肉细胞的肌膜免受收缩引起的损伤。DMD的特点是严重 早期导致危及生命的心脏和呼吸功能障碍的肌肉无力和消瘦 二十多岁。在提高受影响个人的生活质量方面取得了进展；但情况恶化 心功能进展为扩张型心肌病并随后心力衰竭，是主要的 DMD患者的死亡原因。目前的应用主要集中在了解心脏 与肌营养不良症相关的机制和测试已知可改善的新治疗方法 DMD骨骼肌病。我们的研究小组率先发现了几项与 蔗糖蛋白的功能，它是营养不良蛋白-糖蛋白复合体的一个组成部分。我们已经证明了 这种轻微的肉毒杆菌在mdx小鼠的骨骼肌中过表达，而mdx小鼠的骨骼肌中存在突变。 Dystrophin基因，通过稳定一种名为 泛素-糖蛋白复合体，其功能类似于营养不良蛋白-糖蛋白复合体。事实上, 我们的研究揭示了Sarcospan在决定细胞表面表达方面具有类似伴侣的功能 层粘连蛋白结合黏附复合体(即营养不良蛋白-糖蛋白复合体、中性粒细胞营养素-糖蛋白复合体和 α7β1整合素)，已知可改善DMD小鼠模型的疾病。萨科斯潘激活Akt 促进肌肉生长和再生的信号通路，为营养不良提供进一步的好处 肌肉。拟议中的实验将测试将萨科司潘引入心肌是否有改善作用。 与肌营养不良症相关的心肌病。我们的研究将检查DMD中的层粘连蛋白结合 相关的心肌病，并揭示Sarcospan是否影响调节 心肌细胞黏附。在我们的初步数据中，我们揭示了一种新的蔗糖缺乏的心脏表型。 我们将研究Sarcospan是否对多重心脏挑战具有心脏保护作用。这个 该提案的结果将改变我们对DMD心脏发病机制的理解，并提供必要的 对基于草珊瑚的治疗方法的发展的洞察。

PROJECT ABSTRACT Duchenne muscular dystrophy (DMD), the most common form of dystrophy, is caused by mutations in the dystrophin gene that result in loss of dystrophin protein and the entire dystrophin-glycoprotein complex, which protects the sarcolemma of muscle cells from contraction-induced injury. DMD is characterized by severe muscle weakness and wasting that leads to life-threatening cardiac and respiratory dysfunction in the early twenties. Progress has been made to enhance the quality of life of affected individuals; however, deterioration of cardiac function progresses to dilated cardiomyopathy with subsequent heart failure and is the primary cause of mortality in DMD individuals. The current application is focused on understanding the cardiac mechanisms associated with muscular dystrophy and testing new treatments that are known to ameliorate DMD skeletal muscle disease. Our research group has pioneered several key discoveries related to the function of sarcospan, an integral component of the dystrophin-glycoprotein complex. We have demonstrated that mild sarcospan over-expression in skeletal muscle of mdx mice, which possess a mutation in the murine dystrophin gene, rescues muscular dystrophy by stabilizing expression of a complex of proteins called the utrophin-glycoprotein complex that is functionally analogous to the dystrophin-glycoprotein complex. In fact, our studies are revealing a chaperone-like function for sarcospan in determining the cell surface expression of laminin-binding adhesion complexes (i.e. dystrophin-glycoprotein complex, utrophin-glycoprotein complex, and α7β1 integrin) that are known to ameliorate disease in DMD mouse models. Sarcospan activates the Akt signaling pathway that promotes muscle growth and regeneration, providing further benefit to dystrophic muscle. The proposed experiments will test whether introduction of sarcospan into heart muscles ameliorates cardiomyopathy associated with muscular dystrophy. Our studies will examine laminin-binding in DMD associated cardiomyopathy and reveal whether sarcospan affects laminin-binding receptors that regulate cardiomyocyte adhesion. In our preliminary data, we reveal a new cardiac phenotype in sarcospan-deficient mice and we will investigate whether sarcospan is cardioprotective to multiple cardiac challenges. The outcomes of the proposal will change our understanding of DMD cardiac pathogenesis and provide necessary insight for development of sarcospan-based treatments.