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的修饰物，2)更好地定义 肌营养不良患者心肺功能障碍的整合。Ltbp4，编码基因 潜伏的转化生长因子结合蛋白，最初被定位为肌营养不良症的修饰物 策略。在老鼠身上发现的这种修饰物，也被证明与人类肌肉的结果有关 营养不良。在上一个资助期，发现了第二个修饰基因，即Anxa6基因。 编码膜联蛋白A6。膜联蛋白结合含磷脂的膜对钙作出反应。 利用超分辨共聚焦显微镜显示，Annexin A6被精确地招募到 损伤后肌膜破坏。在其他类型的细胞中，膜联蛋白A1被认为是一种关键的 先天免疫反应。肌营养不良蛋白或肌糖蛋白基因突变导致肌膜 不稳定。肌膜的反复断裂，就像在许多形式的肌营养不良症中发生的那样， 触发一系列细胞内和细胞外效应。在骨骼肌中，这些事件通常是 与炎症有关，这会加速疾病的进程。在心肌中， 对炎症的研究较少。最近的数据表明，长期使用糖皮质激素治疗有 对DMD患者的心肺功能的益处。较新的数据支持使用矿物皮质激素 受体拮抗剂可改善心脏和潜在的呼吸功能。因此，我们将调查 修饰剂，特别是膜联蛋白A6和膜联蛋白A1的作用机制及其对类固醇和 盐皮质激素受体阻滞剂。我们还将研究肌肉改良剂之间的相互作用。 营养不良。在最后一个目标中，我们将研究一种新的右室肌层修饰轨迹。 营养不良。在心力衰竭中，右心室是生存的关键决定因素，而在肌营养不良症中，右心室是生存的关键决定因素 伴随的呼吸功能不全还会损害右心室。确定以下目标的路径 右心功能可能有助于改变心肺和骨骼肌功能障碍的进程 肌肉营养不良症。

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.