Molecular basis of telomere dysfunction in cardiac dystrophy

项目概要/摘要 杜氏肌营养不良症（DMD）是最常见的儿童形式的肌营养不良症， 肌营养不良蛋白基因的突变。DMD与肩关节和呼吸肌的早期丧失有关 妥协，其次是心脏并发症的发作。虽然心肌病是一个主要原因， 在DMD患者的死亡中，大多数治疗干预集中在骨骼肌治疗上。我们最近 显示端粒功能障碍与肌营养不良蛋白突变一起导致显著的结构和 功能性心脏缺陷的小鼠，与所有的标志，看到在DMD患者。这里提出的研究 将研究营养不良心肌细胞中端粒诱导的病灶（Aim 1），确定未知的 端粒机制导致心力衰竭（目的2），并确定额外的端粒功能， 端粒蛋白（Aim 3）。了解心脏营养不良进展的机制， 提供新的治疗可能性。这些研究也将为今后的研究奠定基础， 类似的端粒机制在其他心血管疾病。

Project Summary/Abstract Duchenne Muscular Dystrophy (DMD) is the most common childhood form of muscular dystrophy and arises from mutations in the dystrophin gene. DMD is associated with early loss of ambulation and respiratory muscle compromise, followed by the onset of cardiac complications. Although cardiomyopathy is a major cause of death in DMD patients, most therapeutic interventions have focused on skeletal muscle therapies. We recently showed that telomere dysfunction in conjunction with the dystrophin mutation leads to significant structural and functional cardiac defects in mice, with all of the hallmarks seen in DMD patients. The studies proposed here will investigate telomere induced foci in dystrophic cardiomyocytes (Aim 1), identify the role of unknown telomeric mechanisms leading to cardiac failure (Aim 2) and determine the extra-telomeric function of a telomere protein (Aim 3). Understanding the mechanism acting in the progression of cardiac dystrophy will provide new therapeutic possibilities. These studies will also form the foundation for future investigation of similar telomeric mechanisms in other cardiovascular diseases.