对肌动球蛋白收缩力在胆小管周期性运动中细胞动力学作用机制的探究

Bile canaliculi (BC) periodic movement is important to drive bile flow, whose failure can lead to cholestasis. It has been reported that BC periodic movement involves bile secretion and actomyosin contractility surrounding BC, and Radixin is required for the linkage of F-actin to plasma membrane as well as the correct localization of bile secretary transporters at BC. However, the interaction of these 3 factors and their roles in regulating BC dynamics remain unclear. Our preliminary results showed that F-actin dynamics associate the changes of BC volume and blebs occur at BC membrane in hepatocytes culture in collagen sandwich. It suggested that actomyosin contractility counteracts the hydrostatic pressure generated by bile secretion, and also implied the mediating role of Radixin in this process. Using live imaging technology, we plan to investigate: (1) the specific roles of actomyosin contractility and bile secretion in BC periodic movement; (2) the mechanism of regulating BC movement by the interaction between actomyosin contractility and bile secretion; (3) the specific functions of Radixin in blebs and BC movement. This study enables us to understand in depth the mechanobiological mechanism of BC dynamics, and even the pathological causes of cholestasis.

胆汁流动失效诱发胆汁淤积，而胆小管周期性运动是胆汁流动的驱动力。研究表明，肌动球蛋白收缩力与胆汁分泌都是胆小管周期性运动的必要因素，而Radixin在连接肌动蛋白至细胞膜的同时，还驱使胆汁分泌蛋白定位于胆小管。然而针对这三者间的相互作用及其调控胆小管周期性运动的相关机制缺乏深入研究。我们的前期结果显示：胆小管的体积变化与肌动球蛋白收缩力的动力特征在时间空间上都有紧密的联系。观测到的胆小管膜上小泡证实了肌动球蛋白收缩力反作用于胆汁分泌形成的胆小管内液体静压力，也暗示了Radixin在这一过程中的介导作用。本项目拟在预实验基础上，利用活细胞成像技术来研究（1）肌动球蛋白收缩力以及胆汁分泌在胆小管运动中的角色；（2）这两者相互作用从而调控胆小管运动的机制；（3）Radixin在膜上小泡形成以及胆小管运动过程中的具体功能。这些结果能够帮助我们更深入地理解胆小管周期性运动的细胞动力学机制乃至胆汁淤积

研究表明，肌动球蛋白收缩力与胆汁分泌都是胆小管周期性运动的必要因素。然而这其中的具体相关作用机制缺乏深入研究。我们的结果显示：肌动球蛋白收缩力的动力学与胆小管的体积变化存在着较为紧密的联系。本项目利用活细胞成像技术，生物化学等技术研究了（1）F-actin的动力学在胆汁分泌和胆小管运动中的角色；（2）F-actin的动力学在细胞中对线粒体自噬的调节作用以及相关机制。这些结果能够帮助我们更深入地理解F-actin的细胞动力学机制以及生物学意义。