Molecular mechanisms of telomere function in muscle stem cells

项目总结/摘要 杜氏肌营养不良症（DMD）是最常见的儿童形式的肌肉萎缩症。 营养不良和由营养不良基因突变引起。DMD的特征在于： 进行性骨骼肌变性，坏死肌纤维的局灶性组的存在， 肌肉肥大和血清肌酸激酶水平高。而 超过 集中 已取得的进展 在过去的十年里，关于DMD的潜在治疗，目前的策略是 治疗骨骼肌，不考虑卫星细胞。 H p 我们 最近证明端粒缩短是营养不良肌干的区域特征， 小鼠和DMD患者在非常年轻的时候就已经有了MuSC。研究 在这里提出将研究 确定 干细胞在其活小鼠的天然组织环境中， MuSC中端粒缩短的细胞后果（Aim 1）。这项建议会 还研究了NF-κB和端粒之间以前未知的串扰（目的2），并将 确定端粒蛋白在肌营养不良症进展中的功能（目标3）。 了解干细胞功能衰竭与端粒之间的分子联系 缩短将提供潜在的替代方法，以绕过长期使用皮质类固醇 目前正在使用的治疗方法。

Project Summary/Abstract Duchenne Muscular Dystrophy (DMD) is the most common childhood form of muscular dystrophy and arises from mutations in the dystrophic gene. DMD is characterized by progressive skeletal muscle degeneration, the presence of focal groups of necrotic myofibers, muscle hypertrophy and high levels of serum creatine kinase. While over focused progress as been made the last decade with respect to otential treatments for DMD, current strategies are on treatment of skeletal muscle and do not take satellite cells into consideration. h p We recently demonstrated that telomere shortening is a district feature of dystrophic muscle stem cells (MuSCs) in both mice and DMD patients already at a very young age. The studies proposed here will study determine stem cells within their native tissue environment of live mice and will the cellular consequence of telomere shortening in MuSCs (Aim 1). This proposal will also investigate a previously unknown crosstalk between NF-κB and telomeres (Aim 2) and will determine the function of a telomeric protein in the progression of muscular dystrophy (Aim 3). Understanding the molecular the link between stem cell functional exhaustion and telomere shortening will provide potential alternative methods to bypass the use of long-term corticosteroid treatment currently in use.