微丝骨架调控纤毛膜蛋白转运的机制

初级纤毛是一种不动的、突出于细胞表面的天线样细胞器，主要由中心体衍生的基体、微管和纤毛膜组成。初级纤毛感知外界刺激并介导多种信号通路，而其异常会导致一系列发育疾病和肿瘤。申请人前期发现鞭毛内运输蛋白复合体IFT-A选择性转运一系列膜蛋白到初级纤毛，并受到微丝骨架的拮抗；但微丝骨架如何精细调控了这些纤毛膜蛋白的转运还知之甚少。申请人将主要利用哺乳动物细胞模型，并结合前沿成像和生化手段来研究这一问题。拟从以下四个方面展开：1）分析微丝骨架和纤毛膜蛋白转运的关联；2）鉴定微丝骨架调控纤毛膜蛋白转运的路径；3）研究微丝骨架调控纤毛膜蛋白转运的分子机理；4）探索微丝骨架调控的纤毛膜蛋白转运在特定细胞分化中的功能意义。综上，这些研究不仅能揭示纤毛膜蛋白的关键调控机制和在细胞分化水平上的生理学意义，还能为未来发现发育疾病和肿瘤的新靶点提供强有力的支持。

Primary cillium is a non-motile, antenna-like organelle protruding from the cell surface. It is mainly composed of centriole-derived basal body, microtubules, and ciliary membrane. Primary cilium senses external cues and transduces various signaling pathways, and its abnormality leads to a series of developmental diseases and cancer. We previous showed that the intraflagellar transport complex-A (IFT-A) is essential for the selective entry of several membrane cargoes into primary cilium, but the actin cytoskeleton antagonizes this transport. However, how the actin cytoskeleton precisely regulates the transport of these ciliary membrane proteins is poorly understood. Using mammalian cell models, combined with state-of-art imaging and biochemistry tools, our four specific aims are: 1) To analyze the links between actin cytoskeleton and transport of ciliary membrane proteins; 2) To identify the actin cytoskeleton-regulated transport routes of ciliary membrane proteins; 3) To investigate the molecular mechanisms governing the transport of ciliary membrane proteins by the actin cytoskeleton; 4) To explore the functions of actin cytoskeleton-controlled transport of ciliary membrane proteins during specific differentiation process. Together, our study will not only unravel the key regulation mechanisms of ciliary membrane proteins and their physiological roles, but also provide strong support to find new targets for development diseases and cancer.