γ-tocotrienol（GT3）对dko DMD小鼠肌肉干细胞的保护作用

由Dystrophin抗肌营养不良蛋白基因突变引起的杜氏/伯氏进行性肌营养不良症（DMD/BMD）到目前尚未见有效的治疗方案。激素治疗为较常用临床治疗选择，但其疗效不佳；细胞治疗和基因治疗还只是处于动物实验阶段，前景并不容乐观。我们和其他小组试验结果显示肌肉干细胞异常在DMD模型小鼠发病过程中起重要作用，主要表现为DMD模型dko小鼠肌肉干细胞内氧自由基(ROS)产生增加和细胞衰老。本研究将对不同年龄dko小鼠肌肉干细胞的功能和表型进行分析，包括肌肉干细胞体外克隆形成、体内干细胞移植、ROS、细胞衰老、细胞凋亡、DNA损伤和细胞周期等。γ-tocotrienol（GT3）能有效抗氧化和抗凋亡，对造血干细胞损伤有显著保护作用。我们将用GT3对不同年龄dko小鼠处理后，结合体外克隆形成和体内细胞移植试验对肌肉干细胞功能和表型进行分析。同时，结合基因表达分析其作用机制，探索有效的DMD治疗途径。

Although we and others have established stable methods to diagnosis (prenatal and genetic) Dys (Dystrophin anti-dystrophin) gene mutation Duchenne / Becker muscular dystrophy (DMD / BMD) mediated by Dystrophin gene mutation, no effective treatment regimen has been.developed so far. Hormone therapy is more commonly used in the clinical treatment of choice while its efficacy is poor. Cell therapy and gene therapy is only at the stage of animal experiments and the outlook is not optimistic. We and other groups have shown that abnormal muscle stem cells might play an important role in the pathogenesis of DMD disease. Our results indicate that muscle stem cells have higher oxygen free radicals (ROS) and cellular senescence in DMD dko mouse model compared to normal mice. This project will systematically analyze muscle stem cell function and phenotypes in different ages of DMD mice, including in vitro muscle stem cell colony forming ability, in vivo stem cell transplantation, ROS, cell senescence, apoptosis, DNA damage and cell cycle. It is well known that γ-tocotrienol (GT3) has capacities to effective antioxidant, anti-apoptosis and protect hematopoietic stem cell against stress. We will therefore use the GT3 to treat dko mice at different ages. Combining with in vitro colony formation and in vivo cell transplantation, we will illustrate muscle stem cell function. To provide further exploration of effective DMD treatment, we will analyze muscle stem cell phenotypes after GT3 treatment and elucidate the underpinning molecular mechanisms through the related gene expression analysis.