遗传易感因子RNF213通过泛素化下调caveolin-1介导外泌体途径导致烟雾病早期非动脉粥样硬化性血管狭窄/闭塞形成的机制研究

烟雾病是东亚儿童和青壮年脑卒中的重要病因，发病机制未明。我们前期研究发现RNF213基因与烟雾病的发生密切相关，敲除该基因可下调血管内皮细胞小窝蛋白caveolin-1，影响细胞生物学特性并介导外泌体miRNA的改变，且rnf213a基因敲除或重要功能区域缺失的斑马鱼可出现颅内血管狭窄及异常。据此我们提出假说：RNF213通过下调caveolin-1介导的外泌体途径导致烟雾病早期非动脉粥样硬化性血管狭窄/闭塞形成。本课题拟采用分子细胞生物学技术和最新的斑马鱼高速显像技术，从分子、细胞和模式生物水平探索RNF213通过泛素化IBTK/RING1/RNF40下调caveolin-1，后者经外泌体miRNA途径介导血管内皮细胞、平滑肌细胞和巨噬细胞的功能改变，促使烟雾病早期血管病变形成，从外泌体这个新视点阐明烟雾病早期非动脉粥样硬化性血管狭窄/闭塞的发生机制，为烟雾病的防治提供新思路。

Moyamoya disease is an important cause of stroke in children and young adults in East Asia, and its pathogenesis is unknown. Our previous research found that the RNF213 gene is closely related to the occurrence of moyamoya disease. Knockout of this gene can down-regulate caveolin-1 in endothelial cell, affect cell biological characteristics and mediate changes of miRNAs in exosomes. And the zebrafish with rnf213a gene knockout or important domains missing had intracranial stenositic and abnormal blood vessels. Therefore we hypothesize that RNF213 leads to the formation of non-atherosclerotic vascular stenosis/occlusion at an early stage of moyamoya disease by down-regulating the caveolin-1 mediated exosome pathway. This project intends to use molecular cell biology technology and the latest zebrafish high-speed imaging technology from molecular, cellular and model biological levels to explore that RNF213 through the ubiquitination of IBTK/RING1/RNF40 to down-regulate caveolin-1, which mediates the functional changes of vascular endothelial cells, smooth muscle cells and macrophages through miRNA pathway in exosomes, promoting the formation of abnormal vascular phenotypes at an early stage of moyamoya disease. This project will elucidate the mechanism of non-atherosclerotic vascular stenosis/occlusion at an early stage of moyamoya disease from a new perspective about exosomes and provide new ideas for the prevention and treatment of moyamoya disease.