有性生殖过程纤毛与细胞外膜泡细胞器互作网络建立和调控的分子机理

Primary cilia are antenna-like cellular organelles protruding from cell surfaces. The primary cilia provide specialized cellular compartments for interactions with the extracellular milieu and regulation of cellular pathways. The defects of cilia lead to a numbers of common or rare human diseases affecting multiple major organs. The role of primary cilium in its central functions depends on dynamic regulation of ciliary membrane protein composition, yet we know little about the membrane events that regulate ciliary membrane protein trafficking in the organelles. Our preliminary studies showed that ciliary membrane sheds thousands of extracellular microvesicles containing signaling receptors during cilium-generated signaling. These microvesicles adhered along the lengths of the cilia of the target cells and induced expressions of genes in the target cells. The interaction network of ciliary membrane, microvesicles and ciliary membrane of target cells is a novel organelle interaction network. Based on our preliminary data, we propose to investigate the trafficking mechanisms of ciliary microvesicle precursor proteins from cell body to the cilium and the regulations of the shedding of microvesicles from ciliary membrane. Meanwhile, we will determine the composition of the ciliary microvesicles. Furthermore, we will elucidate the regulations of communication signaling pathway based on the ciliary membrane-microvesicles interaction network. The main purpose of the proposed studies is to investigate the initiation and maintenance of the newly defined ciliary membrane-microvesicles organelle interaction network, and to study their physiological functions of in communications between cells. The studies of this project will provide new insights into the regulation and biological function of organelle interactions.

纤毛是一种突起于细胞表面的天线状细胞器，参与细胞信号传递和外界环境感知。纤毛缺陷导致众多常见和罕见的人类疾病，波及多种主要器官。纤毛膜组分的动态调控对纤毛功能的实现至关重要，但是其膜组分的调控方式还知之甚少。申请人的前期工作显示，纤毛膜可以释放富含受体分子的细胞外膜泡，通过这些膜泡与靶细胞纤毛膜结合，传递细胞信号，激活靶细胞基因表达，这种纤毛膜-细胞外膜泡-靶细胞纤毛膜作用模式是一种新颖的细胞器互作方式。本项目将在前期工作的基础上，明确纤毛释放的细胞外膜泡的前体成分从细胞体到纤毛、从纤毛膜到膜泡的转运机制；鉴定这些富含信号分子的细胞外膜泡的构成成分；阐释纤毛与细胞外膜泡的相互作用实现细胞通讯的分子通路。本项目旨在研究纤毛膜-细胞外膜泡-靶细胞纤毛膜这一细胞器互作网络的建立和维持机制，揭示其实现细胞通讯功能的分子机理，拓宽我们对细胞器互作及其生物学的认识。

真核生物纤毛是一种突起于细胞表面的膜包被的天线状细胞器，参与细胞信号调控和外界环境感知。纤毛结构和组分的异常导致众多常见和罕见的人类疾病，波及多种主要脏器。纤毛膜组分的动态调控对纤毛功能的实现至关重要，但是其膜组分的调控方式还知之甚少。本项目的工作主要关注一种新的细胞器互作体系：细胞内膜系统想纤毛膜提供前体物质，纤毛膜可以释放富含受体分子的外泌体膜泡，通过这些膜泡与靶细胞纤毛膜结合，激活靶细胞基因表达，这种细胞内膜-纤毛膜-外泌体膜泡-靶细胞纤毛膜作用模式是一种新颖的细胞器互作方式。本项目的实施：（1）明确了纤毛膜来源细胞外膜泡的来源，并明确了其从细胞内膜到纤毛膜，再从纤毛膜释放的运输途径；（2）鉴定了细胞内膜-纤毛膜-纤毛来源膜泡这一细胞器互作体系建立和维持的多个关键调控分子；（3）发现了纤毛过渡区在此细胞器互作体系中重要地位；（4）建立了多个测试体系，为纤毛来源细胞外膜泡的研究提供了实验方法；（5）研究了此细胞器互作体系在细胞通讯过程的重要作用；（6）结合人类遗传学、动物模型、病人来源细胞等工具，证明了细胞内膜-纤毛膜-纤毛来源膜泡这一细胞器互作体系在人类健康中的重要作用。在本项目经费的支持下，发表以前两位基金号标注的SCI论文共计四篇，包括Genetics in Medicine、Nature Communications等期刊。总而言之，项目关注细胞内膜-纤毛膜-细胞外膜泡-靶细胞纤毛膜这一细胞器互作网络的建立和维持机制，揭示其实现细胞通讯功能的分子机理，并阐明了这一互作机制的生理意义和对人类健康的作用，拓宽我们对细胞器互作及其生理意义的认知。