低剂量辐射适应性中Nrf2调控DNA损伤修复的机制研究

With the rapid development of nuclear technology in agriculture, medicine, life sciences and other fields, the health concerns of low dose radiation (LDR) have become increasingly prominent. DNA damage and repair of cells are the key to the health effect of low dose radiation. Among low-dose radiation biological effects, LDR induced Adaptive Response (RAR) is thought to provide transient protection to cells through activating intracellular DNA damage repair pathway, but the detailed molecular mechanism of how low dose radiation activated DNA repair remains to be further confirmed. In our previous study as well as others, low dose radiation was found to induce the activation and function of transcription factor NF-E2-related factor 2 (Nrf2) which play a central role in LDR induced adaptive response. In the preliminary experiment, it was found that inhibition of Nrf2 gene significantly affected the expression of Rad51 in DNA homologous repair. Therefore, through interferes the expression of Nrf2 with shRNA, and Rad51 gene with siRNA, the purpose of this project is to study the interaction between activation of Nrf2 and Rad51 in DNA damage repair under LDR, and elucidate the molecular mechanism of RAR. Based on this molecular mechanism, we further explore the impact of LDR on radiotherapy of tumors. This project intends to provide new ideas for the protection of LDR and give suggestions for the rational use of low-dose radiation in clinical practice.

随着核技术广泛应用，低剂量辐射（LDR）的健康问题日益凸显。细胞DNA损伤及其对损伤的修复是低剂量辐射健康效应的关键。低剂量辐射适应性中认为低剂量辐射能激活细胞内DNA损伤修复途径而对细胞起短暂的保护作用，但对低剂量辐射激活DNA修复途径的详细分子机制仍不十分清晰。在我们及他人的研究中发现，低剂量辐射可诱导细胞内抗氧化转录因子Nrf2转录功能活化而发挥保护作用，且在预实验中发现Nrf2基因的表达与否显著影响DNA同源修复中Rad51的表达。因而，本项目通过构建Nrf2低表达细胞系及对Rad51基因表达的干扰，研究低剂量辐射作用下Nrf2的活化与DNA损伤修复中Rad51的相互作用关系，阐明低剂量辐射诱导适应性的分子机制，并从这一分子机制入手，探索低剂量辐射诱导的适应性对肿瘤放疗的影响。拟通过以上研究为低剂量辐射的防护、及临床上合理利用低剂量辐射提供新的思路和手段。

随着核技术在医学和日常生活中的广泛应用，辐射暴露的健康问题日益凸显。细胞DNA损伤及其对损伤的修复是辐射健康效应的关键。细胞内DNA损伤修复途径及抗氧化应激途径对细胞起保护作用。在我们及他人的研究中发现，低剂量辐射可诱导细胞内抗氧化转录因子Nrf2转录功能活化而发挥保护作用，但是Nrf2活化对细胞DNA损伤及其对损伤的修复影响的分子机制仍不十分清楚，这一方面对环境中辐射暴露的健康风险难以评估，另一方面也对放射治疗中辐射敏感性缺乏认识。因而，本项目通过构建Nrf2低表达细胞系以及自由基清除剂的加入来进一步确认Nrf2与细胞DNA 损伤修复之间的关系，阐明其中的分子机制。实验中发现辐射后细胞内Nrf2的活化与DNA的损伤修复同时发生，Nrf2的基因抑制能有效提高细胞在辐射或其他DNA 损伤诱导剂作用下的DAN损伤，进一步的研究表明Nrf2不仅发挥抗氧化功能，同时通过直接影响Rad51表达参与同源重组修复途径。本项目通过以上研究为辐射的防护、及临床上如何提高辐射敏感性提供新的思路和手段。