β-Sarcoglycan在mSOD1介导ALS骨骼肌病变中的机制研究

项目名称： β-Sarcoglycan在mSOD1介导ALS骨骼肌病变中的机制研究

项目编号： No.81200882

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 神经系统疾病、精神疾病

项目作者： 胡俊

作者单位： 中国人民解放军第三军医大学

项目金额： 23万元

中文摘要： 肌萎缩侧索硬化症（ALS）是一种进展迅速的神经系统疾病，患者平均寿命为2-5年，缺乏有效的临床治疗手段。SOD1突变被认为是其发病的关键分子事件，但具体机制尚不清楚。我们前期研究发现了一种新的SOD1基因突变类型（mSOD1），在证实其可降低神经元活性，同ALS发病密切相关的基础上，发现骨骼肌细胞跨膜蛋白β-Sarcoglycan（β-SG）可与mSOD1发生相互作用。提示mSOD1可直接作用于骨骼肌细胞。国外研究报道也证实骨骼肌是SOD1突变的靶器官，但具体作用机制未见报道。我们推测，mSOD1与β-SG发生相互作用，引起细胞膜稳定性下降和钙离子内流、下调nNOS活性，从而导致了肌肉的损害和萎缩。本项目拟在细胞和在体动物水平上调控β-SG的表达，探讨其对骨骼肌细胞的影响及机制，进一步论证β-SG是否作为一种共性效应分子，在不同原因ALS骨骼肌病变中发挥作用，为ALS的治疗提供新的靶点。

中文关键词： 肌萎缩侧索硬化症家系；铜-锌超氧化物歧化酶；突变；神经元；转基因小鼠

英文摘要： Amyotrophic Lateral Sclerosis(ALS) is a fatal neurodegenerative disease with rapid progress .With no effective treatment for ALS, the patients' life expectancy is only 2-5 years. Although the exact molecular mechanisms are unclear, mutations in the SOD1 gene is thought to be the key molecular factors associated with ALS. We found a new SOD1 gene mutation type (mSOD1) in the ALS family. Preliminary experiments confirmed that the expression of mSOD1 can reduce the activities of neurons, suggesting that mSOD1 may contribute to the pathogenesis of the family. The interaction protein is β-Sarcoglycan（β-SG） which is the transmembrane glycoproteins providing protection of the sarcolemma and closely related to the muscle membrane stability. We can infer that mSOD1 have direct effects on skeletal muscle. It has proven that that skeletal muscle is a primary target of the mutation of SOD1, but the mechanism is unclear. We hypothesized that the interactions between mSOD1 and β-SG leads directly to skeletal muscle damage in ALS patients, by producing the membrane instability that produces increased intracellular calcium as well as disrupted nitric oxide signaling. In this project, our team plans to research its influence on skeletal muscle cells and its mechanism in cells and vivo level through regulating β-SG expression, to

英文关键词： Familial amyotrophic lateral sclerosis；Cu/Zn superoxide dismutase；mutation；neurons；transgenic mice