多酚药物治疗中毒应激的经典机制为抑制氧化损伤。我们发现白杨素比其他多酚药物的抗中毒应激作用强，可能存在抗氧化损伤外的新机制。前期工作发现: 1)端粒是染色体的脆性位点，是中毒应激的DNA损伤靶点；2)原创性设计以端粒为靶点的细胞模型高通量筛选药物，发现白杨素能保护端粒。本项目拟深入研究：1）用基因毒性药物和氧化中毒模型证明白杨素不仅有多酚药物的作用，抑制应激诱导衰老，还特异性抑制端粒损伤和复制衰老；2）用3D细胞打印的模拟组织、SOUTHERN-BLOT、有丝分裂中期端粒功能、免疫荧光等技术，证明白杨素能增强端粒保护蛋白TRF2功能，维护端粒结构和异染色质属性，缓解中毒应激损伤端粒；3）用TRF2+/-端粒损伤斑马鱼模型和激光片层扫描显微镜，证明白杨素能逆转中毒应激介导的端粒损伤、组织发育异常和个体老化。该项目将在分子水平阐明白杨素保护端粒是协同治疗中毒应激的新途径，为中毒治疗提供新思路。

Inhibition of oxidative damage of the toxicity stress is the classical mechanism of polyphenols. We found that the anti-stress effect of chrysin is more effective than other polyphenol drugs. This suggests a potential new antioxidant mechanism. Previous work showed that: 1)telomeres are fragile sites of chromosomes and are usually targeted by toxic stress; 2) we have previously designed the original cellular model for high through put screening drugs and small moleculars targeting telomeres, and discovered that chrysin protects telomeres. This project aims to further prove that: 1)chrysin not only inhibits the toxicity stress induced cell senescence like the other polyphenols but also inhibits replicative senescence induced by genotoxic drugs; 2)we will use 3D cell printing technology, SOUTHERN-BLOT, mitotic metaphase chromosome with in situ hybridization of telomere probes to detect telomere function and immunofluorescence techniques to study the mechanism of chrysin in inhibiting replicative senescence and we propose that this is due to its role of protecting telomeres, particular its role in promoting telomeric protein TRF2 in the maintenance of telomere structure and function; 3) we will use zebrafish model of telomere dysfunction and light sheet scanning laser microscopy system to study that chrysin can reverse the effects of toxic stress in the embryo development and tissue or individual aging. The project will clarify the new mechanism of anti-toxic stress of chrysin at the molecular level, a new strategy of synergistic treatment through the protection of telomeres, which will provide new ideas in the toxicolgoy and treatment.