BK多瘤病毒（BKV）基因整合引发的VP1/LTAg表达失衡在移植后诱发泌尿系统疾病的作用机制研究

移植受者中BK多瘤病毒（BKV）感染-再激活发生率高，是造成移植物和泌尿系统结构和功能损伤的重要原因和移植领域的重、难点，然而其致病机制仍不明确。我们的前期研究发现：BKV的整合普遍存在；病毒血尿症患者中的整合位点多位于基因间且呈一过性富集，而整合导致病毒或宿主基因组的关键结构改变会引起细胞生物学特性改变。在此基础上，我们提出假说：BKV通过整合使宿主关键基因表达紊乱，导致或协同泌尿系相关疾病发生；病毒衣壳蛋白1/大T抗原（VP1/LTAg）表达失衡及其变化趋势可反映疾病进程。拟通过BKV相关疾病的临床样本和离体BKV感染模型，探究BKV整合介导的融合基因结构变异，筛选并验证特异性融合基因谱，进一步解析在宿主基因表达紊乱条件下受累组织VP1/LTAg于疾病不同阶段的变化趋势及其临床意义，为明确BKV相关泌尿系统疾病的发病机制、建立针对BKV持续性感染及转归的精准干预及早期防治奠定基础。

There is a high incidence of infection-reactivation phenomenon of BK polyomavirus (BKV) in transplant recipients, which is an important cause of structural and functional damage of the graft as well as the urinary system, and thus a key and difficult point in the field of transplantation. However, the pathogenesis is still unclear. Our previous study revealed the universal integration of BKV DNA in human genome. In viremia and viruria patients, integration sites were mostly located in intergenic regions and presented transient enrichment. However, the integration can transform the biological characteristics of cells by interfering key structures of virus or host genome. Based on these findings, we therefore speculate that BKV disrupts the expression of host key genes through integration, which leads to development of urologic diseases. And the disease progression can probably be reflected by expression imbalance and change tendency of VP1/LTAg. By studying the clinical samples associated with BKV-related diseases and in vitro BKV infection models, we aimed to investigate the specific structural variants in fusion genes induced by BKV integration, screen and verify the specific fusion gene expression profiles, and further analyze the change tendency of the Viral Protein 1/Large T Antigen (VP1/LTAg) expression in the involved tissue at different stages of the disease under the condition of host gene expression disorder and the clinical significance of it. This study would lay a foundation for clarifying the pathogenesis of BKV-associated urologic diseases and establishing precise intervention and early prevention and treatment for BKV persistent infection and its clinical outcomes.