PI3K/Akt/mTORC1信号通路在小鼠IgA肾病进展中的作用及靶向治疗

项目名称： PI3K/Akt/mTORC1信号通路在小鼠IgA肾病进展中的作用及靶向治疗

项目编号： No.81500529

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 田继华

作者单位： 山西医科大学

项目金额： 17万元

中文摘要： PI3K/Akt/mTORC1信号通路在细胞增殖、分化中具有重要地位，通路的紊乱会引起一系列的疾病。大量的研究证明，肾脏疾病的发生发展也与PI3K/Akt/mTORC1通路有着密切的关联，而其在IgA肾病中的作用尚待进一步研究。本项目旨在研究mTORC1信号通路在IgA肾病中的作用, 探讨mTORC1与系膜细胞增殖的关系；同时联用雷帕霉素、ERK1/2抑制剂Binimetinib (ARRY-438162)对IgA肾病小鼠进行靶向治疗。本项目首先建立IgA肾病小鼠模型，检测mTORC1信号通路蛋白的表达，用特异性敲除系膜细胞Tsc1基因的小鼠（mTORC1异常激活），观察mTORC1可以引起的肾脏明显病理改变；分离肾小球系膜细胞，测定各周期与凋亡蛋白；观察单用或联用药物对IgA肾病的效果，并检测mTOR及ERK1/2通路蛋白，研究两条信号通路的相互作用，探讨其作用机制。

中文关键词： IgA肾病；靶向治疗；PI3K/Akt/mTORC1信号通路

英文摘要： PI3K/Akt/mTORC1 signaling pathways in cell proliferation and differentiation, has the important status, pathway disorders can lead to a series of disease.A large number of studies have demonstrated that kidney disease and PI3K/Akt/mTORC1 pathway is closely associated, and its role in IgA nephropathy remains to be further research.This project aims to study the role of mTORC1 signaling pathways in IgA nephropathy, to investigate the relationship between the mTORC1 and mesangial cell proliferation;At the same time, combination of rapamycin and ERK1/2 inhibitors Binimetinib (ARRY-438162) for targeted therapy of IgA nephropathy in mice. First, IgA nephropathy in mice model were established to detect protein expression of mTORC1 signaling pathways; with a specificity Tsc1 gene knockout in mesangial cells of mice (abnormal mTORC1 activation), observe significant pathological changes in kidney; the glomerular mesangial cells were cultured to measure cycle and apoptosis protein; Observe the effect of alone or combination drugs to IgA nephropathy, and detect mTOR and ERK1/2 channel proteins, study the interaction of the two signaling pathways, explore its action mechanism.

英文关键词： IgA nephropathy;targeted therapy;PI3K/Akt/mTORC1 signaling passway