常染色体显性多囊肾病(ADPKD)是最常见的单基因遗传病，其中约85％患者由多囊蛋白1功能异常引起，其对ADPKD发生的作用机制至今未能完全阐明。我们在前期研究中发现补体替代途径在ADPKD患者和模型动物多囊肾组织中异常活跃，其补体表达谱与自身免疫性疾病如IgA肾病、狼疮性肾炎等不同，抑制其补体表达或活性显著延缓多囊肾病进展，说明补体替代途径过度活化与多囊肾病进展相关。本项目拟在前期研究基础上采用基因敲除、过表达或突变细胞和动物模型，应用RNA干扰、分子探针及荧光素酶报告基因等多项技术进一步探讨多囊蛋白1对补体替代途径启动因子－补体B因子的调控作用及机制，以证实多囊蛋白1经JAK2-STAT3通路，或多囊蛋白1胞内羧基端游离肽段P30作用STAT3，调控补体B因子的假设，以进一步阐明多囊肾病的发病和进展机制，为临床寻找干预多囊肾病的新靶标提供新颖的理论和实验依据。

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic inherited disease, 85% of ADPKD patients are caused by the dysfunction of polycystin-1. However, the pathogenesis of ADPKD caused by polycystin-1 dysfunction still remains further exploration. In our previous study, we found excessive activation of the alternative complement pathway in the kidney tissue of ADPKD patients and animal models of polycystic kidney disease. The expression pattern of alternative complement pathway in ADPKD was different from autoimmune diseases such as IgA nephropathy, and lupus nephritis. Inhibiting the expression and activity of the alternative complement pathway significantly delayed the progression of polycystic kidney disease, indicating that the excessive activation of alternative complement pathway in the polycystic kidney was associated with the progression of the disease. Based on our previous findings, we will further explore the role and the mechanism of polycystin-1 in the regulation of expression of complement factor B, the initial factor of alternative complement pathway, by utilizing various biological techniques such as RNA interference, molecular probes and luciferase reporter gene. We will prove the hypothesis that polycystin-1 regulates the expression of complement factor B through JAK2-STAT3 pathway, or through polycystin-1 C-terminal cleavage fragment P30 together with STAT3. Our study will further elucidate the pathogenesis of polycystic kidney disease, and will provide a cutting-edge theory and experimental basis for finding novel intervention targets in the polycystic kidney disease.