过表达hTSC1导致的肌萎缩小鼠模型的建立及其分子机制的研究

发布时间：2018-05-02 04:53

本文选题：表达 + hTSC1　；参考：《复旦大学》2006年博士论文

【摘要】： 许多严重的疾病都伴随着肌萎缩，例如AIDS、癌症和糖尿病。Insulin／IGF信号传导通路对于调节肌肉的生长具有非常重要的作用。最近的研究发现了一个肿瘤抑制蛋白，TSC(Tuberous Sclerosis)复合物，可以抑制Insulin／IGF信号转导途径。TSC复合物是由TSC1和TSC2两种蛋白组成的。通过建立TSC1转基因小鼠，我们在小鼠骨骼肌中特异性地高表达人的TSC1蛋白，，并观察到了肌萎缩的表型。进一步分子机理的研究表明，hTSC1在蛋白水平上稳定了内源性的TSC2。细胞内功能性TSC复合物水平的增加，抑制了Insulin／IGF-AKT-mTOR信号转导途径，从而导致了肌肉细胞尺寸减小，呈现出了肌肉萎缩的表型。我们还发现，改变TSC复合物的活性只影响了细胞的生长，而并没有影响糖代谢的功能。我们的研究还证明Insulin／IGF信号有效地调节在细胞内TSC复合物的水平。因此TSC1转基因鼠为我们了解肌肉萎缩的分子机制提供了一个很好的动物模型。
[Abstract]:Many serious diseases are accompanied by muscle atrophy, such as AIDS, cancer and diabetes. Insulin / Insulin / IGF signaling pathway plays a very important role in regulating muscle growth. Recently, a tumor suppressor protein (TSC) complex was found to inhibit the Insulin/IGF signal transduction pathway. TSC complex is composed of two proteins, TSC1 and TSC2. By establishing TSC1 transgenic mice, we specifically overexpressed human TSC1 protein in skeletal muscle of mice, and observed the phenotype of muscle atrophy. Further studies on molecular mechanism indicated that hTSC1 stabilized endogenous TSC2 at protein level. The increase of intracellular functional TSC complex inhibits the Insulin/IGF-AKT-mTOR signal transduction pathway, resulting in the reduction of muscle cell size and the phenotype of muscle atrophy. We also found that changes in the activity of TSC complexes only affected cell growth, but did not affect the function of glucose metabolism. Our study also demonstrated that Insulin/IGF signals can effectively regulate the level of TSC complexes in cells. Therefore, TSC1 transgenic mice provide a good animal model for understanding the molecular mechanism of muscular atrophy.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2006
【分类号】：R-332

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