SH3-PX-BAR类蛋白在钙化性主动脉瓣狭窄发生发展中的作用机制研究

钙化性主动脉瓣狭窄（CAVS）是一种退行性变的瓣膜疾病，早期表现为瓣膜增厚，基质分泌过多，其中机制仍不清。本课题旨在探索参与CAVS发生发展的重要蛋白分子。Sorting nexin蛋白是内小体功能蛋白，负责蛋白转运和囊泡运输。我们采用蛋白质谱分析了钙化和正常人瓣膜组织蛋白，发现Sorting nexin蛋白成员中，仅同属SH3-PX-BAR类蛋白的SNX9，SNX18和SNX33在人钙化瓣膜中表达显著下调。SNX18敲除小鼠的主动脉瓣膜比正常小鼠的基质胶原纤维明显增多。因此我们假设以SNX18为代表的SH3-PX-BAR蛋白在瓣膜钙化中发挥了重要作用。我们将借助基因敲除小鼠、体外培养人和小鼠瓣膜间质细胞进一步明确瓣膜间质细胞中SH3-PX-BAR蛋白的功能和细胞表型，从囊泡重塑等方向解释其调控机制。本课题将揭示该退行性变疾病的新的发病机制。

Calcific aortic valve stenosis (CAVS) is a degenerative valvular disease, with valve incrassation and hyperfibrosis, but its mechanism still needs to be clarified. Sorting nexin family proteins are the functional proteins localized at endosomes, in charge of the protein trafficking and vesicular transport. Our project is aim to find out the key proteins in the progression of CAVS. We have found that the expression of the SH3-PX-BAR proteins including SNX9, SNX18 and SNX33 were heavily downregulated in the human calcific valves, compared with the normal ones. And the aortic valves of SNX18 knockout mice got thicker than those wildtypes. We hypothesis that the SH3-PX-BAR proteins may play an important role in the progression of CAVS. Next, we will verify the functional phenotype of these proteins, and explain the exact mechanism. This project will uncover another important factors in the disease.