间充质干细胞蛋白多糖Agrin促进尿失禁功能恢复的机制研究

项目来源

国家自然科学基金(NSFC)

项目主持人

江海红

项目受资助机构

温州医科大学

项目编号

81670695

立项年度

2016

立项时间

未公开

研究期限

未知 / 未知

项目级别

国家级

受资助金额

51.00万元

学科

医学科学-泌尿系统-泌尿系统疾病研究新技术与新方法

学科代码

H-H05-H0511

基金类别

面上项目

关键词

蛋白多糖 ; 干细胞 ; 产伤 ; 生物标志物 ; 尿失禁 ; urinary incontinence ; stem cell ; proteoglycan ; biomarker ; birth injury

参与者

王思齐;林峰;李海燕;陈洪德;黄航;李仕;叶翔翔;林琦;蒋海波

参与机构

温州医科大学

项目标书摘要:利用间充质干细胞(mesenchymal stem cells,MSCs)受趋化因子归巢到损伤部位是干细胞治疗研究的重要策略之一,我们发现CCL7因子在产伤后压力性尿失禁(stress urinary incontinence,SUI)动物尿道局部大量表达,并对MSCs在尿道局部聚集活化显著。据此通过SILAC等蛋白筛查发现并确认CCL7刺激后MSCs的Agrin及下游通路蛋白显著升高;进一步临床上对手术治疗SUI病人筛查CCL7及Agrin,发现Agrin表达显著减少和曾有严重产伤后SUI显著相关。CCL7可能通过Agrin使MSCs活化并促进产伤后SUI恢复。本研究拟在此基础上进行相应的临床、细胞、分子、及动物实验,论证CCL7/Agrin表达缺陷预示产妇发生产伤后SUI危险增加,解析CCL7通过Agrin调控下游通路的分子机制;为进一步深入研究MSCs防治产伤后及后期SUI提供基础。

Application Abstract: Use of mesenchymal stem cells(MSCs)homing to damaged tissue by local specific chemokine is one of the important strategies for stem cell treatment research.We found cytokine CCL7 expression increase in significance in urethra on stress urinary incontinence(SUI)animal model of childbirth injury,which can increase local gathering and activating MSCs to urethra significantly.Then we used SILAC screening and related testing found and confirmed MSCs agrin and its downstream pathway proteins increases in significance after CCL7 stimulation.Furthermore,in clinic,we found there was a significant correlation for SUI patients whose Agrin responsive expression defect during the anti-SUI sling procedure with SUI patients who have had serious SUI after childbirth injury.Therefore,Agrin might help SUI recovery through the mechanism of CCL7 interacting with Agrin to gather and activate MSCs at local injured urethra.In this study,utilizing clinical trial and related mocular and SUI animal model experiments;we will confirm if the defects on CCL7 or Agrin reactive expression after maternal injury to urethra will increase the risk SUI after childbirth injury.We will also clarify the detail mechanism of CCL7 interact with Agrin and its downstream pathway regulation.This investigation will provide an important basis for understanding and further in-depth study of the MSCs for alleviating maternal SUI and later SUI incidence and prevalence.

项目受资助省

浙江省

项目结题报告(全文)

间充质干细胞(mesenchymal stem cells,MSCs)受趋化因子趋化聚集到损伤部位是干细胞治疗研究的重要策略之一,通过本课题研究,我们确认了CCL7因子在产伤后压力性尿失禁(stress urinary incontinence,SUI)动物模型的尿道局部表达显著升高,CCL7干预能够显著增强MSCs在尿道局部的聚集和活化;我们阐明了CCL7主要是通过Agrin来促进局部MSCs的聚集和活化,并可以促进产伤后SUI的控尿功能恢复;论证了其主要是通过CCL7-MSCs-Agrin通路,并影响下游Agrin-Lrp4-MuSK轴信号分子机制来活化。进一步的延伸研究中,我们还发现了MSCs聚集活化后对尿道局部微环境的局部成纤维细胞代谢有显著影响,这将为我们继续深入研究打下基础依据,也为进一步临床开发应用MSCs及其分泌物为基础的细胞学治疗尿失禁提供基础理论依据。

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