MDM2介导的有丝分裂灾难- - -糖尿病肾病足细胞损伤的新机制

项目名称： MDM2介导的有丝分裂灾难- - -糖尿病肾病足细胞损伤的新机制

项目编号： No.81470964

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张春

作者单位： 华中科技大学

项目金额： 73万元

中文摘要： 足细胞损伤和缺失是糖尿病肾病（DN）发病机制的关键环节，然而高糖所致足细胞损伤的机制尚未完全阐明。研究表明，作为终末分化细胞的足细胞一旦重新进入细胞周期发生有丝分裂将致其死亡-即有丝分裂灾难。MDM2是一种E3泛素连接酶，可通过多种信号通路调控细胞周期和有丝分裂。我们的前期研究发现，DN患者肾组织中存在异常有丝分裂的足细胞，并伴有MDM2及其下游分子TERT表达上调，且后者表达强度与足细胞数目呈负相关；体外研究显示，高糖可上调足细胞MDM2和TERT表达，提示MDM2介导的有丝分裂灾难可能是DN足细胞数目减少的重要原因。在前期研究基础上，本项目拟采用体外细胞模型、足细胞特异性MDM2基因敲除的DN小鼠模型和临床DN患者肾活检标本为研究对象，探讨足细胞有丝分裂灾难在DN进程中的病理生理意义及MDM2-TERT信号通路在足细胞有丝分裂灾难发生中的关键作用，以期为DN的早期防治提供新的理论依据。

中文关键词： 有丝分裂灾难；MDM2；糖尿病肾病；足细胞

英文摘要： Podocyte injury and loss are essential events of diabetic nephropathy. However, the mechanism of podocyte damage is not completely understood. It is well known that terminally differentiated cells are restricted in 'post-mitosis' state and cannot enter the cell cycle to divide, otherwise the outcome is catastrophic. The death caused by abnormal mitosis is defined as mitosis catastrophe. Murine double minute 2(MDM2) is a positive regulator of cell cycle and modulates the process of mitosis through several signaling pathways. Our preliminary data showed that mitotic podocytes are detected in patients diagnosed as diabetic nephropathy, simultaneously the expression of MDM2 and its downstream effector telomerase reverse transcriptase (TERT) are both upregulated. Moreover, the abundance of TERT is negative correlated with the number of podocytes. The expression of MDM2 and TERT in podocytes is also elevated significantly upon exposure to high glucose in vitro. Taken together, we hypothesize that in diabetic condition the mitosis catastrophe of podocytes induced by MDM2 is the major factor account for podocyte depletion. On the basis of our previous experiments we are going to investigate the significance of podocyte mitosis catastrophe in the pathogenesis of diabetic nephropathy and the effect of MDM2-TERT signaling pathway in above processes in cultured human podocytes, podocyte conditional MDM2 knockout mice and patients with diabetic nephropathy. By this investigation, we expect to clarify the molecular mechanism of podocyte injury and depletion in the early stage of diabetic nephropathy and shed light on the exploration of its effective therapies.

英文关键词： Mitotic Catastrophe;Murine Double Minute 2;Diabetic Nephropathy;Podocytes