FOXD1/AXL信号轴调控胶质瘤干细胞放疗抵抗及糖酵解代谢的分子机制研究

胶质瘤干细胞（GSCs）对于肿瘤复发及治疗抵抗性的形成具有重要意义。前期研究中我们发现转录因子FOXD1和受体酪氨酸蛋白激酶AXL在胶质瘤中高表达而且随肿瘤级别增加递增，放疗可以诱导GSCs对FOXD1和AXL的表达增高，敲低FOXD1能够降低GSCs对AXL的表达并能抑制其糖酵解代谢能力。本研究拟此基础之上首先通过调控FOXD1和AXL在GSCs的表达明确二者在GSCs的互作规律及其对GSCs放疗抵抗和糖酵解代谢的影响；然后研究FOXD1/AXL下游信号分子STAT3和PDK3在上述过程中的作用，进一步阐明FOXD1/AXL调控GSCs放疗抵抗和糖酵解代谢的具体机制；最后检测放疗诱导发生凋亡神经球细胞所释放的外泌体中AXL含量变化情况并研究其对GSCs表型的影响效果及规律，从而揭示FOXD1/AXL信号轴调控GSCs放疗抵抗和糖酵解代谢的分子机制，为胶质瘤临床靶向治疗方案研发提供新思路。

Glioma stem-like cells (GSCs) play a crucial role in tumor recurrence and the formation of therapy resistance. We found that transcription factor FOXD1 and receptor tyrosine kinase AXL were highly expressed in glioma and increased with the tumor grade. Irradiation can induce elevated expression of FOXD1 and AXL in GSCs. Knockdown of FOXD1 in GSCs can reduce their AXL expression and glycolysis capability. Based on these observations, we first plan to investigate their interaction and explore their roles in the regulation of GSCs radio-resistance and glycolysis metabolism through knocking down and overexpressing FOXD1 and AXL in GSCs. Second, we aim to explore the mechanism of FOXD1/AXL regulating the radio-resistance and glycolysis metabolism in GSCs by studying the roles of their downstream signaling molecules, STAT3 and PDK3, in the process mentioned above. In addition, we plan to measure the concentration of AXL protein in the exosomes released by irradiation induced apoptosis neurosphere cells and study the effect of these exosomes on GSCs phenotypes to clarify the molecular mechanism of FOXD1/AXL axis on the regulation of radio-resistance and glycolysis in GSCs. Moreover, this study will provide ideas for developing new strategies of targeted therapy in glioma.