Molecular mechanisms of telomere function in muscle stem cells

项目摘要/摘要 Duchenne肌营养不良症(DMD)是儿童时期最常见的肌肉疾病 营养不良，由营养不良基因突变引起。DMD的特点是 进行性骨骼肌退行性变，坏死性肌纤维局灶性群的存在， 肌肉肥大和高水平的血清肌酸激酶。而当 完毕 聚焦 过去十年 论治疗 关于潜力 骨骼肌和DO 已经取得了进展 DMD的治疗，当前的策略 不考虑卫星细胞。 是 我们 最近证实，端粒缩短是营养不良肌干的一个区域性特征 小鼠和DMD患者在很小的时候就已经有了细胞(MuSCs)。这些研究 建议在此进行研究 确定 干细胞在其活的天然组织环境中 骨髓间充质干细胞端粒缩短的细胞后果(目标1) 老鼠 和 将要 。这项提议将 还研究了核因子-κB和端粒之间以前未知的串扰(目标2)，并将 确定端粒蛋白在肌营养不良进展中的作用(目标3)。 理解干细胞功能衰竭与端粒之间的分子联系 缩短术将提供潜在的替代方法，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 the last decade on treatment with respect to potential of skeletal muscle and do progress has been made treatments for DMD, current strategies not take satellite cells into consideration. are 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 the cellular consequence of telomere shortening in MuSCs (Aim 1) mice and will . 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.