PPK/Flagellin介导UPEC诱导肾草酸钙结石形成的作用机制研究

草酸钙结石的具体发病机制尚不明确。既往的研究多认为草酸钙结石的形成是机体代谢异常所致，而本课题组的前期结果却提示尿路中的尿路致病大肠埃希菌（UPEC）可能是草酸钙结石形成的重要诱因：UPEC的分泌产物可以显著促进草酸钙晶体成核、聚集及粘附于肾小管上皮细胞。进一步通过针对UPEC分泌产物的鉴定筛选，发现作为细菌生物学功能的核心调控分子多聚磷酸盐激酶（PPK）及其调控分子鞭毛蛋白（Flagellin）在UPEC诱导的草酸钙结石形成与进展过程中发挥了重要作用。本项目拟通过体外和体内模型，从晶体形成、细胞损伤和晶体-细胞粘附等多个角度深入阐述UPEC通过PPK/Flagellin通路诱导草酸钙结石形成的分子机制，对于分析UPEC在草酸钙结石形成过程中的具体机制具有重要意义，有助于为草酸钙结石的发病机制研究提供新的实验依据和研究思路，并为草酸钙结石的临床防治提供新的干预靶点和策略。

Escherichia coli (UPEC) is the most common bacterium found both in urine and stone culture from calcium oxalate stone patients, but the role and mechanism of UPEC in the formation of calcium oxalate stone is still unclear. Our recent results showed that secretions of UPEC could promote the calcium oxalate crystal aggregation and crystal-cell adhesion in vitro. After further screening experiment, we indicated that polyphosphate kinase (PPK), a core molecule regulating biological functions of UPEC, mediate the promoting effect of UPEC on calcium oxalate crystal aggregation and crystal-cell adhesion through accelerating flagellin secretion. These results illuminated the intra-bacterial PPK/Flagellin pathway may mediate the promoting effect of UPEC on calcium oxalate stone formation, but the extra-bacterial downstream mechanisms is still need to be explored. In this study, we will further investigate the extra-bacterial downstream mechanisms of of flagellin regulating crystal nucleation, aggregation and adhesion in vitro and in vivo. This study is going to provide experimental data and new theoretical basis for the pathogenesis, clinical prevention and treatment of calcium oxalate stones.