MAD2B介导的细胞周期再进入在FSGS足细胞损伤中的作用及其机制

足细胞损伤和缺失是原发性局灶节段性肾小球硬化（FSGS）的主要病理特征。研究表明，细胞周期再进入是导致FSGS进程中足细胞损伤和缺失的早期细胞事件，然而其发生机制尚未明确。有丝分裂阻滞缺陷蛋白---MAD2B是调控细胞周期的重要分子。我们的前期研究发现，FSGS小鼠模型足细胞MAD2B表达升高，且其表达强度与足细胞数目呈负相关；而体外敲低MAD2B可抑制细胞周期再进入和足细胞损伤，提示MAD2B是介导足细胞细胞周期再进入的关键分子。进一步生物信息学分析和预实验结果表明，MAD2B的磷酸化及其泛素化降解可能受ATM调控。在上述前期研究基础上，本项目拟采用体外细胞模型、足细胞特异性基因敲除和转基因小鼠等为研究对象，深入探讨MAD2B介导的细胞周期再进入在FSGS进程中的病理生理作用及ATM对MAD2B的调控机制，期望深化对FSGS发病机理的认识，并为其早期防治提供新的理论依据。

Podocyte injury and loss are characteristic features of focal segmental glomerulosclerosis. It has been well documented that cell cycle re-entry of post-mitotic podocytes is involved in the development of podocyte injury and loss. However, the mechanism of cell cycle re-entry and its pathogenic role in FSGS has not been fully clarified. Mitotic arrest deficient-like 2 (MAD2B) is an important molecule involved in the regulation of cell cycle. Our preliminary data showed that the expression of MAD2B was elevated significantly in the podocyte area of FSGS mice, which was negatively correlated with the number of podocytes. In addition, inhibition of MAD2B in cultured podocytes prevented cell cycle re-entry and subsequent cell injury, suggesting that MAD2B plays a vital role in inducing cell cycle re-entry of podocytes. According to bioinformatic analysis, we found that MAD2B might be phosphorylated by ATM (Ataxia-Telangiectasia Mutated) kinase, which is necessary for its degradation. On the basis of these previous experiments, we plan to investigate the significance of MAD2B-mediated cell cycle re-entry of podocytes in the pathogenesis of FSGS and the role of ATM in regulating MAD2B phosphorylation, by using cultured podocytes and conditional knockout/transgenic mice. Through these studies, we expect to deepen the current understanding of the pathogenesis of FSGS and provide evidence for it early intervention.