m6A甲基化修饰调控四氢叶酸合成途径在放射性皮肤损伤中的作用及机制研究

Radiation induced skin injury is a common side effect during radiotherapy. Tetrahydrofolate (THF) is the main source of one carbon unit, which provide material for DNA replication and repair. THF is catalyzed by DHFR (dihydrofolate reductase). It is not clear whether tetrahydrofolate synthesis is involved in radiation induced skin injury. Our preliminary experiments revealed that radiation could decrease the level of THF and influence m6A (N6-methyladenosine) demethylase that modifies DHFR mRNA, resulting in the increase of DHFR. Based on these results, we propose the hypothesis that radiation regulates m6A demethylase and influences the m6A modification on DHFR mRNA and its stabilization, solving the problem of THF shortage caused by irradiation and influencing the process of radiation induced skin injury. By using multiple biological approaches, this project is designated to reveal the following issues, both in vitro and in vivo. 1) To uncover the effect of irradiation on THF synthesis pathway. 2) To reveal the regulation of m6A modification on DHFR expression and to uncover the protective role DHFR and THF, both in vitro and in vivo. 3) To ameliorate radiation induced skin injury by activation THF synthesis pathway. This project will lead to a better understanding of radiation induced skin injury and provide new strategies to the treatment of radiation induced skin injury.

放射性皮肤损伤是肿瘤放疗中常出现的副反应。四氢叶酸（THF）是生物体内携带一碳单位的分子之一，能够为DNA复制和修复提供原料。THF由二氢叶酸还原酶（DHFR）催化合成，四氢叶酸合成途径是否参与放射性皮肤损伤的发生亟待研究。本项目预实验发现：电离辐射降低THF水平，同时影响DHFR mRNA的N6-甲基腺嘌呤（m6A）修饰酶，增加DHFR表达。据此我们提出假说：电离辐射调控m6A修饰酶影响DHFR mRNA修饰及稳定性，补充电离辐射破坏的THF，影响放射性皮肤损伤的进展。本项目拟通过多种生物学手段，在细胞及动物水平揭示：1）电离辐射对四氢叶酸合成途径的影响；2）明确m6A修饰对DHFR蛋白表达调控的具体机制，同时在体内体外实验中明确DHFR及四氢叶酸的保护作用；3）通过活化四氢叶酸合成途径实现放射性皮肤损伤的防护。本项目有望更深入了解放射性皮肤损伤的发生机制，为保护皮肤损伤提供理论依据

放射性皮肤损伤是肿瘤放疗中常出现的副反应。四氢叶酸（THF）是生物体内携带一碳单位的分子之一，能够为DNA复制和修复提供原料。THF由二氢叶酸还原酶（DHFR）催化合成，四氢叶酸合成途径是否参与放射性皮肤损伤的发生亟待研究。本项目发现：电离辐射降低THF水平，同时影响DHFR mRNA的N6-甲基腺嘌呤（m6A）修饰酶，改变DHFR表达。电离辐射调控m6A修饰酶影响DHFR mRNA修饰及稳定性，影响放射性皮肤损伤的进展。本项目通过多种生物学手段，在细胞及动物水平揭示：1）电离辐射对四氢叶酸合成途径的影响；2）明确m6A修饰对DHFR蛋白表达调控的具体机制，同时在体内体外实验中明确DHFR及四氢叶酸的保护作用；3）通过活化四氢叶酸合成途径实现放射性皮肤损伤的防护。本项目深入了解放射性皮肤损伤的发生机制，为保护皮肤损伤提供理论依据。