MAPPING MODIFIERS OF CARDIOMYOPATHY IN MUSCULAR DYSTROPHY

摘要 项目2建议1）识别和研究肌营养不良症的修饰剂，2）更好地定义 肌营养不良症患者心肺功能不全之间的整合。Ltbp4基因编码 潜伏性TGF β 1结合蛋白，最初被定位为肌营养不良症的修饰物，使用全基因组 战略在小鼠中鉴定的这种修饰剂也显示出与人类肌肉组织中的结果相关。 营养不良在上一个资助期，第二个修饰因子以Anxa6的形式被鉴定出来， 编码蛋白膜联蛋白A6。膜联蛋白结合含磷脂的膜以响应钙。 使用超分辨率共聚焦显微镜，显示膜联蛋白A6被精确地募集到 损伤后肌膜破裂。在其他细胞类型中，膜联蛋白A1被认为是细胞增殖的关键调节因子。 先天免疫反应肌营养不良蛋白或肌聚糖基因的突变导致肌膜 不稳定肌膜的反复破坏，如发生在许多形式的肌营养不良症， 引发了细胞内和细胞外效应的级联反应。在骨骼肌中，这些事件通常 与炎症有关，这加速了疾病的进程。在心肌中， 炎症的研究较少。最近的数据表明，长期使用糖皮质激素治疗 这一益处延伸至DMD患者的心肺功能。新的数据支持盐皮质激素的使用 受体拮抗剂，以改善心脏和潜在的呼吸功能。因此，我们将调查 修饰剂的作用机制，特别是膜联蛋白A6和膜联蛋白A1，以及它们对类固醇的反应， 盐皮质激素受体阻滞剂。我们还将研究肌肉的修饰剂之间的相互作用， 营养不良在最后一个目的中，我们将研究一个新的修饰位点的右心室肌， 营养不良在心力衰竭中，右心室是生存的关键决定因素，在肌营养不良中， 右心室还受到伴随的呼吸功能不全的损害。确定以下途径： 右心室功能可能有助于改变心肺和骨骼肌功能障碍的过程， 肌肉萎缩症

Abstract Project 2 proposes 1) to identify and study modifiers of muscular dystrophy and 2) to better define the integration between cardiac and pulmonary dysfunction in muscular dystrophy. Ltbp4, the gene encoding latent TGF binding protein, was originally mapped as a modifier of muscular dystrophy using a genomewide strategy. This modifier, identified in mice, was also shown to associate with outcome in human muscular dystrophy. In the last funding period, a second modifier was identified in the form of Anxa6, the gene encoding the protein annexin A6. Annexins bind phospholipid-containing membranes in response to calcium. Using super-resolution confocal microscopy, it was shown that annexin A6 is recruited precisely to the site of sarcolemmal disruption after injury. In other cell types, annexin A1 has been implicated as a key regulator of the innate immune response. Mutations in dystrophin or the sarcoglycan genes lead to sarcolemma instability. The repetitive disruption of the sarcolemma, as occurs in many forms of muscular dystrophy, triggers a cascade of intracellular and extracellular effects. In skeletal muscle, these events are often associated with inflammation, which accelerates the disease course. In cardiac muscle, the contribution of inflammation is less well studied. Recent data suggests that long term treatment with glucocorticoids has benefit that extends to cardiopulmonary function in DMD. Newer data supports the use of mineralocorticoid receptor antagonists to improve cardiac and potentially respiratory function. Therefore, we will investigate the mechanism of action of modifiers, specifically annexin A6 and annexin A1, and their response to steroids and mineralocorticoid receptor blockers. We will also investigate the interactions among modifiers for muscular dystrophy. In the last aim, we will investigate a new modifier locus of the right ventricle in muscular dystrophy. In heart failure, the right ventricle is a key determinant of survival and in muscular dystrophy the right ventricle is additionally compromised by concomitant respiratory insufficiency. Identifying pathways for right ventricular function may help change the course of cardiopulmonary and skeletal muscle dysfunction in muscular dystrophy.