脑胶质瘤恶性程度强、易侵袭、病死率高，迄今无良药可医。溶瘤病毒因可靶向性杀伤肿瘤细胞而倍受重视。我们发现甲病毒M1可靶向性杀伤胶质瘤细胞，而无害于正常细胞，明显延长胶质瘤大鼠的存活。翻译抑制虽为甲病毒共认的杀瘤机制，但其专杀肿瘤细胞的嗜瘤机制不明。我们发现M1感染后（可靶向PI3K和PTEN的）miR29a上调，众所周知PTEN在胶质瘤细胞中多有变异，而正常细胞中无变异，故极可能"在PTEN变异的细胞中，miR29a不能平衡地下调PI3K和PTEN，细胞因'PI3K促活通路'被阻断而死亡"。本研究拟运用基因沉默、过表达等手段确认PI3K通路被阻断在M1嗜瘤机制中的意义，并用WB、报告基因等方法确定miR29a如何双向调控PI3K通路，最后通过干预miR29a确证其在M1嗜瘤机制中的关键作用。本项目对甲病毒专杀肿瘤细胞的嗜瘤机制之阐明将为把其改造成更高效、更特异的溶瘤病毒奠定坚实的理论基础。

Human malignant glioma is a disease with high degree of malignancy, extensive invasion, short course, high death rate, at the same time without effective therapy. The oncolytic virus may specifically kill tumor cells without any harm to normal cells. It has been proved that alphavirus M1 target a variety of glioma cells， induce apoptosis and has a good oncolytic effect on the rat orthotopic glioma model rats. The oncolytic mechanism of alphaviruses, which is inhibiting the intracellular translation, has been gradually been accepted as a consensus. However, for Alphavirus, the reason why it exclusively target tumor cells is largely unknown. According to our results, we proposed an intracellular mechanism underling the tumor-specificity: with PTEN deficiency in most glioma cells, down-regulation activity of miR-29a on PTEN can not work, leaving only its down-regulation activity on PI3K, thereby promoting cell to die. Firstly，this study uses drugs such as LY294002, rapamycin to get the conclusive evidence of the PI3K/AKT pathway in M1 infection, and its impact on viral replication and apoptosis, and uses the WB, the reporter gene analysis method to determine the targeted down-regulation of miR-29a on PI3K and PTEN. The project will provide a scientific basis for clarifing the tumor targeted mechanism of alphavirus; promote M1 developing as an oncolytic virus, and provide theoretical support to the individualized therapy.