Wnt3a通过跨膜蛋白MARVELD3调控质膜完整性影响细胞焦亡在放射性皮肤损伤中的作用及机制研究

放射性皮肤损伤是肿瘤放疗和核事故的常见并发症，严重影响患者的生活质量。MARVELD3是一种新近发现的紧密连接跨膜蛋白，其表达分布对放射性皮肤损伤的影响尚未见报道。本项目前期研究发现：Wnt3a可保护受照射皮肤细胞，维持质膜的屏障功能；转录组测序发现Wnt3a引起受照射皮肤细胞中差异表达的mRNA主要富集于紧密连接，MARVELD3的差异最为显著。据此，我们提出科学假设：Wnt3a通过MARVELD3调控质膜完整性干预电离辐射诱发的皮肤细胞焦亡，减轻放射性皮肤损伤。本项目拟在前期研究的基础上通过多种分子生物学手段在细胞水平和动物模型上进一步诠释：1）Wnt3a对MARVELD3表达分布的影响并验证两者间是否存在相互作用；2）调控MARVELD3维持质膜完整性对细胞焦亡的影响；3）MARVELD3对皮肤细胞放射敏感性及放射性皮肤损伤进展的影响。本项目有望为放射性皮肤损伤提供一种新的防治策略。

Radiation-induced skin injury is a common complication after radiotherapy and nuclear accident, which seriously affects the quality of life of patients. MARVEL Domain Containing 3 (MARVELD3) is a new transmembrane protein of tight junction. Whether its expression and distribution affects the progression of radiation-induced skin injury has not been reported. In our preliminary studies, we found that Wnt3a could protect irradiated skin cells and maintain the barrier function of cytomembrane. The RNA-Seq analysis revealed that the differentially expressed mRNAs in Wnt3a-treated irradiated skin cells were mainly enriched in tight junction, and MARVELD3 showed the most significant differential expression. Therefore, we propose our scientific hypothesis: Wnt3a regulates cytomembrane integrity through MARVELD3 to intervene in the pyroptosis of irradiated skin cells to alleviate radiation-induced skin injury. This project aims to further elucidate the following issues at cellular and animal levels by various molecular biological approaches: 1) The effects of Wnt3a on the expression and distribution of MARVELD3, and further verify whether there is an interaction between the two in vivo and in vitro. 2) The effect of maintaining cytomembrane integrity by MARVELD3 on pyroptosis of irradiated skin cells. 3) The effects of MARVELD3 on the radiosensitivity of skin cells and the progression of radiation-induced skin injury. This project is expected to provide new targets and strategies for the prevention and treatment of radiation-induced skin injury.