OFD1调控的原纤毛在细胞周期和胰腺癌中的机制研究

Studies have shown that various diseases in humans (including cancer), are related to the imbalance of cilia structure and length, and the structure of cilia is in dynamic in the cell cycle. Our previous study found that OFD1 (Oral-Facial-Digital syndrome 1 protein) regulated primary cilia arrests the cell cycle in the G0 / G1 phase in a p53-independent manner, and this cell arrest is not due to DNA damage. Based on this, we speculate that OFD1-regulated priamry cilia may be a new cell cycle checkpoint different from the classic checkpoint, and the disorders of cell cycle are often closely linked with vairety of cancer. However, the molecular mechanisms of OFD1 cell cycle checkpoint and its function and significance in cancer are not yet clear. Therefore, this project will study on the following two scientific issues: 1) clarify the molecular mechanism of primary cilia as a new cell cycle checkpoint; 2) to explore the function of new cell cycle checkpoint in pancreatic cancer and its significance. We believe that elucidation of the molecular mechanisms underlying the cell cycle checkpoints will provide new candidated targets for detection or treatment of cilia related disease and cancer ， and provide a solid theoretical basis for the development of drugs that target cell cycle checkpoints.

研究显示人类许多疾病包括癌症都与纤毛结构、长度的失调相关，而纤毛的结构在细胞周期运转过程中发生动态变化。我们的前期研究结果发现OFD1（Oral-Facial-Digital syndrome 1 protein）调控的原纤毛将细胞周期以不依赖p53的方式阻滞在G0/G1期，且这种细胞阻滞并不是由于DNA损伤造成的。基于此，我们推测OFD1调控的原纤毛是一种区别于经典细胞周期的检查点。而细胞周期的紊乱常常与癌症的发生有密切联系，但目前对于其调控的分子机制及与癌症的相关性尚不清晰。因此，本课题将围绕以下两个科学问题展开研究：1）明确OFD1调控的原纤毛作为细胞周期检查点的分子机制；2）初步探索该检查点在胰腺癌中的功能及意义。我们相信阐明该检查点的分子机制，将为纤毛相关疾病尤其是癌症诊断和治疗提供新的候选靶点，同时为开发靶向细胞周期检查点的药物提供坚实的理论基础。

本研究鉴定了一种新型的细胞周期检查点，激活该检查点，导致正常细胞周期阻滞于G0/G1期，并伴随原纤毛的形成。上述周期阻滞，并不依赖于原纤毛或p53调节的经典通路。在肿瘤细胞中激活该检查点，能有效抑制胰腺癌等肿瘤细胞的增殖。我们结合生物化学、细胞生物学、生物信息学等方法，绘制了关键调控蛋白网络，系统阐明新型周期检查点的机制。并在小鼠水平验证了靶向上述新检查点作为抑制胰腺癌进展的有效性。本研究为肿瘤的预防和治疗提供理论依据和潜在的靶点。