DNA损伤修复与胰腺癌放化疗抵抗密切相关。我们前期通过高通量蛋白质组学筛选技术发现，MBD1与DNA损伤修复有关；深入研究证实，MBD1能被MDC1募集，促进NBS1的磷酸化，进而调控DNA损伤修复及放化疗抵抗；基于蛋白-蛋白相互作用分析及前期研究提示，我们又推测SIRT1是MBD1促进NBS1磷酸化的中间衔接分子，由此提出"MDC1-MBD1/SIRT1-NBS1"功能轴这一新的分子机制。本课题拟在前期研究的基础上，进一步围绕此功能轴开展以下研究：①分析胰腺癌细胞中MDC1、MBD1/SIRT1、NBS1在结构和功能上的联系，对此功能轴进行验证；②在胰腺癌临床样本中检测MDC1、MBD1/SIRT1、NBS1的表达，探讨此功能轴与胰腺癌放化疗抵抗的相关性；③通过体内、体外实验，干预此功能轴，明确其对胰腺癌DNA损伤修复及放化疗抵抗的影响，为临床上胰腺癌放化疗抵抗提供干预和预测的潜在靶点。

It is well acknowledged that DNA damage repair and chemo-radioresistance are closely related in pancreatic cancer. Previously, we had demonstrated that MBD1 was involved in DNA damage repair and chemo-radioresistance by means of a high-throughput proteomic filtering technology. With further research, we found that MBD1 may facilitate NBS1 phosphorylation after recruited by MDC1, which contributed to the modulation of DNA damage repair and the chemo-radioresistance afterwards. Based on our previous study about the protein interactions, we speculated that SIRT1 may have an important role as a connected molecular between MBD1 and phosphorylated NBS1. So we suggest that there is a new molecular mechanism as an axis of MDC1-MBD1/SIRT1-NBS1 to take effect and we are going to carry out some researches on this functional axis as below: 1. Analyze the connection between the MDC1, MBD1/SIRT1 and NBS1 both structurally and functionally in pancreatic cancer for the confirmation of this axis. 2. Determinate the expression of these molecular in clinical specimens to investigate the correlation between this axis and chemo-radioresistance in pancreatic cancer. 3. Disturb this functional axis by some in vitro and in vivo assays for further validation that it can effectively predict the chemo-radioresistance and serve as a potential therapeutic target in pancreatic cancer.