Molecular basis of telomere dysfunction in cardiac dystrophy

项目摘要/摘要 杜氏肌营养不良症(Duchenne Muscle Dystrophy，DMD)是儿童期最常见的肌营养不良症， 来自营养不良蛋白基因的突变。DMD与早期失去行走能力和呼吸肌有关 妥协，随之而来的是心脏并发症的发生。尽管心肌病是导致 对于DMD患者的死亡，大多数治疗干预措施都集中在骨骼肌治疗上。我们最近 研究表明，端粒功能障碍与dystrophin突变一起导致显著的结构性和 小鼠的功能性心脏缺陷，具有DMD患者的所有特征。在这里提出的研究 将研究营养不良心肌细胞中端粒诱导的病灶(目标1)，确定未知的作用 导致心力衰竭的端粒机制(目标2)，并确定端粒外功能 端粒蛋白(目标3)。了解心脏营养不良进展的机制将 提供了新的治疗可能性。这些研究也将为今后对 其他心血管疾病中类似的端粒机制。

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.