PRDX6/Wnt3a复合物调控β-Catenin通路对辐射损伤的影响与机制研究

The prevention and treatment for radiation-induced injury is not only conducive to cancer radiotherapy, but also has practical significance to deal with nuclear accidents. β-Catenin signaling pathway is closed related to tissue repair and regeneration upon injuries, however, its role and regulatory mechanism in radiation-induced injury have not been fully elucidated. In our preliminary study, we found that peroxidase PRDX6 could alleviate radiation-induced injury of normal cells. Moreover, we also found that PRDX6 can interact with Wnt3a and activate β-Catenin signaling pathway. We therefore hypothesize that binding of PRDX6 and Wnt3a stabilizes Wnt3a, which promotes constitutive activation of the β-Catenin signaling pathway and contributes to tissue repair and regeneration after radiation. In this project, we will confirm the above hypothesis: elucidating the mechanism how PRDX6 activates β-Catenin by interaction with Wnt3a. Furthermore, we will also analyze the radio-protective role of PRDX6/Wnt3a complex for mice and human normal cells. This study is expected to reveal the role of β-signaling pathway in radiation injury and its regulatory mechanism by PRDX6/Wnt3a complex, which is likely to provide a new approach for the treatment of radiation-induced injury.

辐射损伤的防治不仅有利于癌症放射治疗的顺利进行，而且对于应对核辐射事故具有现实意义。β-Catenin信号通路与损伤修复和组织再生等关系非常密切，但其在辐射损伤中的作用及调控机制仍未完全阐明。我们前期研究发现过氧化物酶PRDX6可减轻正常细胞受到的辐射损伤；PRDX6能与Wnt3a相互作用，并能激活下游β-Catenin信号通路。因而我们提出科学假设：PRDX6与Wnt3a结合后稳定了Wnt3a，促进后者与受体的结合进而激活β-Catenin信号通路，影响辐射后细胞和个体的损伤修复。本项目拟在前期工作基础上验证这一假设：阐明PRDX6与Wnt3a相互作用位点及对β-Catenin的激活机制，进一步揭示PRDX6/Wnt3a复合物对正常细胞和动物个体辐射损伤的影响和机制。本研究有望揭示β-Catenin信号通路在辐射损伤中的作用及PRDX6对其的调控机制，也为辐射的治疗提供新的思路与途径。

随着电离辐射在工业、医疗、科研等领域越来越广泛的应用，人体暴露于电离辐射照射的几率大大增加。一旦暴露于电离辐射，机体正常组织脏器往往发生形态和功能的改变，其中皮肤、胃肠道、肺脏等辐射敏感器官更易发生不可逆的放射性损伤。然而，目前临床上尚缺乏机制清楚、靶点明确的正常组织放射损伤的特效防治药物，因此，十分有必要继续开展正常组织放射损伤的致病分子机制研究。.在物种的进化过程中高度保守的β-catenin信号通路，在动物胚胎的早期发育、器官形成、组织再生等诸多重要生理过程中发挥重要作用。该通路对细胞的多种生物学行为具有调控作用，但其对生物体内皮肤、小肠等器官的辐射敏感性及放射性损伤进展的影响及作用机制尚不明确。本项目采用体、内外放射性皮肤损伤模型深入探究了β-catenin信号通路对皮肤细胞放射敏感性以及放射性皮肤损伤进展的影响及其潜在的作用机制。本研究主要的研究结果发现：电离辐射可激活正常皮肤组织中β-catenin信号通路；采用Wnt3a进一步促进β-catenin通路的信号传导，能够有效降低受照皮肤细胞的凋亡率及细胞内活性氧自由基的水平、促进受照皮肤细胞的迁移；在小鼠放-创复合伤模型中，伤口局部施用Wnt3a可加速伤口的愈合；采用多组学联合生信分析法，初步明确Wnt3a引起受照射皮肤细胞中紧密连接蛋白MARVELD3的表达下调，后续分析发现Wnt3a/ MARVELD3/JNK信号轴参与了放射性皮肤损伤发生进展，干预该信号轴可减轻放射性皮肤损伤。.本项目揭示了放射性皮肤损伤新的潜在分子机制：外源性Wnt3a配体蛋白可促进受照射皮肤细胞中β-catenin信号通路的持续传导，引起皮肤细胞中MARVELD3的表达下调，通过调控皮肤细胞中下游JNK蛋白的磷酸化水平，进而减轻电离辐射导致的皮肤损伤，为治疗放射性损伤提供了一个以β-catenin信号通路为靶点的防治新思路。