肾小管再生过程中细胞启动增殖的关键机制研究
结题报告
批准号:
81800596
项目类别:
青年科学基金项目
资助金额:
22.0 万元
负责人:
赵栓
依托单位:
学科分类:
H0502.泌尿系统损伤与修复
结题年份:
2021
批准年份:
2018
项目状态:
已结题
项目参与者:
袁敏、胡家昌、金是、刘少鹏、欧阳华聪、焦晓燕、耿雪梅、汪小燕
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中文摘要
急性肾损伤(AKI)是临床常见危重症,肾小管上皮细胞凋亡脱落是AKI的主要病理基础,促进肾小管再生是改善AKI预后的关键。肾小管通过幸存上皮细胞或干细胞增殖完成再生,但何种机制启动幸存细胞或干细胞进入增殖周期尚不清楚。钙粘蛋白(E-cadherin)在调控上皮细胞增殖中发挥关键作用,且在AKI早期即显著上调。本项目首先通过AKI动物模型确定肾小管上皮细胞凋亡与幸存上皮细胞或干细胞重新启动增殖之间的时空关系,然后利用国际首创的体外肾小管损伤修复三维模型,通过基因编辑确定E-cadherin在幸存上皮细胞或干细胞增殖选择中的作用,最后确定E-cadherin启动细胞进入增殖的关键信号通路(聚焦Hippo/YAP和EGFR/p-Erk通路)。本项目的顺利完成将揭示肾小管上皮细胞凋亡与启动增殖之间的时空关系和关键分子机制,为促进肾小管再生奠定理论基础,并为生物人工肾的研发提供有力的技术支撑。
英文摘要
Acute kidney injury (AKI) is a major clinical disorder, characterized by sever tubular cells apoptosis and loss associated with rapid worsening of the renal function. Accelerating the regeneration process of injured tubular cells could effectively ameliorate AKI. Regeneration of renal tubule after AKI may occur through multiple mechanisms including the de-differentiation of surviving resident cells and/or the intrinsic ability of resident progenitor cells to proliferate and differentiate into new renal cells, however, molecular mechanism underling the initiation of this process is still unknown. E-cadherin play a key role in the cell-cycle reentry of most kinds of epithelial cells, and is significantly up-regulated in early stage of AKI. In this study, firstly, we will determine the spatio-temporal relationship between cell apoptosis and proliferation in the mouse AKI model. Secondly, an in vitro renal tubule AKI model had been built via three-dimensional culture of renal tubule cells in our previous study. This model will be used to exploited the role of E-cadherin in initiating proliferation of surviving resident cells or progenitor cells. Finally, we determine possible signal pathways, Hippo/YAP or EGFR/p-Erk, that underlining E-cadherin promoting cell-cycle reentry. The successful completion of this project will reveal the spatio-temporal relationship between cell apoptosis and proliferation, and the underlining molecular mechanism which will lay a theoretical function for promoting the regeneration and repair of renal tubules, and provide strong technical support for the development of biological artificial kidney.
肾脏是体内具有再生能力的器官之一。急性肾损伤(AKI)时损伤最严重的近端小管上皮细胞如何启动细胞增殖完成修复尚不清楚。本项目利用小鼠AKI模型、体外近端小管上皮细胞损伤模型对肾脏损伤后近端小管上皮细胞启动增殖的分子调控机制进行研究,发现Cadherin16(CDH16)和N-cadherin(CDH2)是人、小鼠和大鼠近端肾小管上皮细胞中表达的主要钙粘蛋白类型。Cadherin16而不是N-cadherin的降解是近端肾小管上皮细胞诱导周围细胞启动增殖的关键钙粘蛋白。近端小管上皮细胞损伤后引起Cadherin16的降解,通过促进RHBDL2的表达引起EGF的分泌,EGF通过激活p-Erk启动细胞增殖过程。此外,外源添加EGF能够直接促进近端小管上皮细胞启动增殖,为临床促进AKI的修复提供理论和实践依据。
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
RacGAP1 ameliorates acute kidney injury by promoting proliferation and suppressing apoptosis of renal tubular cells
RacGAP1通过促进肾小管细胞增殖和抑制凋亡来改善急性肾损伤
DOI:10.1016/j.bbrc.2020.04.140
发表时间:2020
期刊:Biochemical and Biophysical Research Communications
影响因子:3.1
作者:Weiran Zhou;Shuan Zhao;Sujuan Xu;Zhaoxing Sun;Yiran Liang;Xiaoqiang Ding
通讯作者:Xiaoqiang Ding
DOI:10.3969/j.issn.1672-8467.2021.05.016
发表时间:2021
期刊:复旦学报(医学版)
影响因子:--
作者:张杨;王一梅;姜物华;赵栓;丁小强
通讯作者:丁小强
DOI:10.3389/fmed.2021.782624
发表时间:2021
期刊:Frontiers in medicine
影响因子:3.9
作者:Zhou W;Li Y;Ning Y;Gong S;Song N;Zhu B;Wang J;Zhao S;Shi Y;Ding X
通讯作者:Ding X
DOI:10.1016/j.nefro.2020.06.007
发表时间:2021-03-01
期刊:NEFROLOGIA
影响因子:2.6
作者:Jiang, Wuhua;Wang, Xiaoyan;Zhao, Shuan
通讯作者:Zhao, Shuan
DOI:10.3969/j.issn.1672-8467.2021.02.016
发表时间:2021
期刊:复旦学报(医学版)
影响因子:--
作者:周蔚然;赵栓;丁小强
通讯作者:丁小强
国内基金
海外基金