PHF19上调EXD2促进DNA损伤修复增加胶质瘤放疗抵抗的作用与机制研究

胶质瘤为最常见的原发性脑肿瘤，治疗困难。放射治疗是胶质瘤最有效的治疗手段之一，而临床治疗中普遍存在放疗抵抗现象，常导致疗效不佳，患者预后差。放疗抵抗的分子机制和靶向策略是目前的研究热点。我们前期研究发现，接受放疗的胶质瘤病人中PHF19表达量显著升高，并且过表达PHF19促进胶质瘤细胞的放疗抵抗能力。初步的机制研究表明，PHF19可能通过上调EXD2促进了胶质瘤细胞的同源重组修复进程，从而导致放疗抵抗。本项目拟在多个胶质瘤细胞中对PHF19进行敲除或过表达，通过分子生物学，细胞生物学及小鼠治疗模型，深入研究PHF19在胶质瘤放疗抵抗过程中的作用及其分子机制，阐明PHF19对EXD2的正向调控作用，并探讨靶向PHF19对治疗效果的影响及其临床意义。研究结果将有助于拓展对胶质瘤放疗抵抗调节过程的认识，揭示PHF19上调EXD2促进胶质瘤放疗抵抗的新机制，可能为临床治疗提供新的策略和线索。

Radiotherapy is one of the most effective treatments for gliomas, and radiotherapy resistance is widespread in clinical treatment, which often leads to poor efficacy and poor prognosis for patients. The molecular mechanisms and targeting strategies of radiotherapy resistance are currently a hot research topic. Our previous study found that the expression of PHF19 in glioma patients receiving radiotherapy was significantly increased, and overexpression of PHF19 can promote the resistance of glioma cells to radiation therapy. Preliminary mechanism studies have shown that PHF19 may promote the homologous recombination process of glioma cells by up-regulating EXD2, thereby causing glioma cells to resist radiotherapy. This project intends to knock out or overexpress PHF19 in multiple glioma cells. Through molecular biology, cell biology and mouse models, in-depth study of the role of PHF19 in the process of glioma resistance to radiotherapy and its molecules Mechanism, to clarify the positive regulation of PHF19 on EXD2, and explore the effect of targeting PHF19 on treatment sensitivity and its clinical significance. The research results will help expand the understanding of the regulation process of glioma radiotherapy resistance, reveal a new mechanism by which PHF19 up-regulates EXD2 to promote glioma radiotherapy resistance, and may provide new strategies and clues for clinical treatment.