低剂量放射超敏感性或增强的放射抵抗性(low-dose hyperradiosensitivity/increased radioresistance,HRS/IRR)现象自发现以来,以其潜在临床应用价值，一直是放射生物学领域研究的热点，但发生机制仍不清楚。我们前期发现：HRS/IRR阳性肿瘤细胞在低剂量辐射下错配修复基因MLH1表达及自噬水平显著增加，且在该辐射剂量点细胞由HRS向IRR转变。进一步下调MLH1基因表达或抑制自噬后，细胞呈现HRS现象增强，提示MLH1在低剂量辐射下可通过调控自噬信号通路诱导HRS向IRR转变。本课题拟在此基础上，进一步解析MLH1基因在低剂量辐射下通过自噬信号通路对HRS/IRR现象的作用及机制，在细胞和动物水平观测调控MLH1基因对低剂量辐射放疗敏感性的影响，为HRS/IRR现象奠定新的理论依据，以及低剂量放疗、超分割放疗的个体化临床应用提供实验基础。

Low-dose radiation hypersensitivity or increased radiation resistance (low-dose hyperradiosensitivity/increased radioresistance, HRS/IRR) phenomenon have drawn great interest in the past few years due to its potential clinical value, but its exact molecular mechanisms is still unclear. We previously demonstrated that expression of mismatch repair gene MLH1 and autophagy level in HRS/IRR positive cancer cells were significantly increased after low dose radiation and cells underwent transition from HRS to IRR at the same radiation dose. Moreover, knockdown of MLH1 gene expression or inhibition of autophagy induced enhanced HRS phenomenon in HRS/IRR positive cancer cells, indicating the potential role of MLH1 in the HRS/IRR response via autophagy regulation. In this project, we will further study the molecular basis of MLH1 via autophagy regulation in the HRS/IRR phenomina after low-dose ionizing radiation, and explore the effect of MLH1 modulating on the radiosensitivity. Successful completion of this study should provide new insights into the mechanism of HRS/IRR phenomenon, and provide experimental basis for individualized clinical application of low-dose radiation and hyperfractionated radiotherapy.