高糖调控 Mre11-ATM-Cdc25 通路导致前列腺细胞周期监测点紊乱的机制

糖尿病和列腺癌均为常见重大疾病，危害中老年男性健康。多项研究发现，高血糖可导致前列腺损害并增加高级别腺癌发病风险，但机制未明。我们前期高血糖动物实验与基因芯片检测发现，高糖可下调Mre11 基因的表达。已知MRE11蛋白在修复DNA 损伤及调控细胞周期起重要作用，Cdc25 的表达与前列腺癌的恶性度呈正相关。本项目拟利用基因过表达、siRNA、体外激酶试验、GST 融合蛋白沉降试验等方法，从分子、细胞、动物和临床层面，阐明高糖下调Mre11 表达、并通过“ATM-chk2-cdc25”信号通路抑制G2/M 细胞周期检测点激活的分子机制，为防治高糖所致的前列腺细胞周期紊乱、以及高级别腺癌的发生提供新靶点与新策略，该研究具有重要的意义和研究价值。

Diabetes and prostate cancer are common major disease，which are harmful to the health of middle-aged and old menMultiple studies had shown that high blood glucose can injure the prostate and can increase the risk of high grade prostate cancer. However, the molecular mechanisms remains unknown. Our previous animal studies and microarray results showed that, high glucose decreased the expression of Mre11 gene. It is known that MRE11 plays important roles in the DNA damage repair and cell cycle regulation. Expression of Cdc25 was positively correlated with the maligancy of prostate cancer. By using molecular, cellular, animal and human sample tissues stuies and experimental methods such as gene overexpression, siRNA,in vitro kinase assay,and GST pull down, we aimed to investigate the role of the signaling of "ATM-chk2-cdc25" which is regulated by Mre11 and high glucose, in the control of the G2/M cell cycle checkpoint. We also aimed to provide new targets and new strategies for the preventionand therapy of dysfunction of cell cycle,high incidence of high grade prostate cancer in the prostate as caused by the high glucose. . Diabetes and prostate cancer are both modern common diseases，and bring harmful damage to men's health. It has important significance and study value to study the molecular mechanism of lesions of the prosate caused by high blood glucose.