NIMA相关蛋白激酶CNK4调控纤毛稳定性和长度的分子机制研究

纤毛/鞭毛是存在于细胞表面以微管结构为基础的保守细胞器。纤毛具有多种多样的生物学功能，包括参与细胞运动、进行信号传导、调控细胞分化和发育。纤毛的组装和维持都受到复杂而精细的调控，纤毛的结构和功能的缺陷将会导致一系列纤毛疾病。在前期的研究中，我们发现衣藻中NIMA相关蛋白激酶CNK4对纤毛的稳定性和长度具有调控作用。CNK4缺失后细胞组装形成长纤毛，并且在纤毛上形成膨胀突起进而逐渐卷曲脱落。cnk4纤毛的电镜图片显示卷曲的纤毛中微管结构不稳定，发生了卷曲和解体松散。CNK4缺失后纤毛内甲基化修饰蛋白和IFT蛋白增加，并且IFT运动发生频繁的停滞。本项目拟研究CNK4调控纤毛微管稳定性的作用机理和CNK4调控纤毛长度的作用机理，进而揭示CNK4蛋白激酶对纤毛稳定性和长度的具体调控机制，进一步完善纤毛组装和维持的调控理论，该研究将会为纤毛疾病的诊断和治疗提供新的线索和理论支持。

Cilia/flagella are conserved MT-based organelles projecting from cell surface. Cilia are involved in a variety of cell processes including cellular motility, signal transduction, cell differentiation and development. Ciliary assembly and maintenance are complexly and precisely regulated. Defects in ciliary structure and function have been shown to cause a serious of genetic diseases and developmental disorders termed ciliopathies. In previous research, we find that a Chlamydomonas Nrk, CNK4, regulated ciliary stability and length. The cnk4-null mutant exhibited long flagella, with formation of flagellar bulges. The flagella gradually became curled, leading to flagellar loss. Electron microscopy shows that the curled flagella involved curling and degeneration of axonemal microtubules. cnk4 mutation resulted in flagellar increases of methylated proteins and IFT trains, and IFT trains frequently stalled in the flagella. This project is focused on the research that how CNK4 regulates ciliary microtubule stability and ciliary length to uncover the mechanism of CNK4 regulating ciliary length and stability, and improve our knowledge of the mechanism underlying ciliary length and maintenance. The findings of the research will provide new clues and theoretical support for diagnosis and therapy of ciliopathies.