透皮短肽修饰的PRDX-6复合丝素蛋白在放射性皮肤损伤防治中的作用及机理研究

Ionizing radiation is used extensively to treat many different types of cancer. However, radiotherapy may significantly injure the skin and profoundly impair its function. Therefore, radiation-induced skin injury remains a serious concern that may limit the duration and the delivered dose of radiation. Previously,we have demonstrated the important role of Peroxiredoxin-6（PRDX-6）pathway in ameliorating this damage in rats. The supplementation of PRDX-6 may contribute the prevention and mitigation of the radiation-induced skin injury. We have screened a transdermal domain that can mediate the transdermal delivery of the fusion proteins. In this project, we will prepare transdermal PRDX-6 fusion protein and further fuse it with nucleus/cytoplasm/mitochondrial location peptides. These fusion proteins with different subcellular location of PRDX-6 will be used to compare the differential effect and mecanism in counteracting irradiation-induced skin damage. We will also combine the PRDX-6 fusion proteins with silk-based protein. The complex will be used to treat radiation-induced skin injury in animal models (rat and pig models). And we will further explore its mechanism including reactive oxygen species (ROS), cell apoptosis and cell senescence. This project is likely to provide a new approach for the treatment of radiation-induced skin injury.

放射性皮肤损伤是肿瘤放射治疗和放射性核事故等之后常见的并发症，严重影响患者的生活质量。我们前期发现在放射线的作用下， Peroxiredoxin-6（PRDX-6）通路是影响皮肤损伤的重要因素。因而如能对清除自由基和抗氧化的PRDX-6酶进行补充，则可以高效清除皮肤自由基和氧化损伤，从而能有效预防或治疗放射性皮肤损伤。我们通过优化蛋白质转导结构域筛选到了一种能介导大分子蛋白质透皮的短肽，并已获得国家发明专利。我们拟将该短肽与PRDX-6进行融合，赋予了PRDX-6透皮能力后并进一步分别融合细胞核/细胞质/线粒体定位肽，从自由基、细胞衰老、凋亡等通路揭示上述PRDX-6融合蛋白亚细胞定位对电离辐射的保护的异同。利用仿生丝素蛋白纳米纤维组织工程材料对上述融合蛋白进行装载，进而应用于体外培养的皮肤细胞和动物模型（大鼠和小型猪）的放射性皮肤损伤防护与治疗，为放射性皮肤损伤的防护和治疗提供新的方法。

放射性皮肤损伤是肿瘤放射治疗、骨髓移植预处理、放射性核事故等之后常见的并发症，严重影响患者的生活质量。本项目在前期研究基础上进一步阐明了PRDX6调控放射性皮肤损伤进展的机制。本项目实施过程中，筛选鉴定了能介导大分子蛋白质透皮的短肽(KKLFPKGVFTKELPSGKKYLR)；阐明了miR-214/ Peroxiredoxin-6（PRDX-6）通路通过抑制细胞凋亡、减少辐射引起的自由基等减轻放射性皮肤损伤的机制。此外，沉默PRDX6可显著增加肿瘤细胞对于电离辐射的敏感性。本项目还制备了可透皮的PRDX-6融合蛋白复合丝素蛋白组织工程材料。本项目的开展，为放射性皮肤损伤的防治提供新的思路与途径。项目执行期间，共发表标注项目资助基金号的论文9篇。发表的论文包括Int J Radiation Oncology*Biology*Physics（红皮杂志），J Cancer等杂志，获得教育部二等奖一项(第二完成人)，获国家发明专利1项、实用新型专利4项，申请发明专利3项，培养研究生四名。