Wnt1通过LKB1/PGC1-α通路调控小胶质细胞炎性活化对早产鼠脑白质损伤的保护作用

批准号:
82001601
项目类别:
青年科学基金项目
资助金额:
24.0 万元
负责人:
高金枝
依托单位:
学科分类:
新生儿相关疾病
结题年份:
2023
批准年份:
2020
项目状态:
已结题
项目参与者:
高金枝
国基评审专家1V1指导 中标率高出同行96.8%
结合最新热点,提供专业选题建议
深度指导申报书撰写,确保创新可行
指导项目中标800+,快速提高中标率
微信扫码咨询
中文摘要
脑白质损伤是早产低出生体重儿的严重并发症之一。Wnt1抑制小胶质细胞炎性活化是保护脑白质受损的关键途径,但其中的机制尚不甚明晰。申请人前期研究发现Wnt1除了经Wnt/β-catenin信号途径,还可能经Wnt/LKB1/PGC1-α通路调控小胶质细胞炎性活化,改善脑白质损伤。本项目拟深入解析Wnt1通过LKB1/PGC1-α通路调控小胶质细胞炎性活化的机制及其对早产鼠脑白质的保护作用。构建含小胶质细胞特异性启动子的LKB1-shRNA慢病毒载体和SIRT1-siRNA,靶向沉默小胶质细胞中LKB1和SIRT1基因表达。然后检测小胶质细胞炎性活化、Wnt/LKB1/PGC1-α信号通路关键蛋白表达。动物模型验证Wnt1通过LKB1/PGC1-α通路调控小胶质细胞活化机制及其对早产鼠脑白质损伤的保护作用。本项目将为Wnt1治疗宫内感染致早产鼠脑白质损伤机制提供新的理论依据。
英文摘要
White matter injury is one of the serious complications of premature and low birth weight newborns. Wnt1 secreted by the neurovascular unit inhibits the inflammatory activation of microglial cells, which is a critical way to protect brain white matter injury. Still, the exact mechanisms underlying the anti-inflammatory activation of microglial cells induced by Wnt1 is still not very clear. The preliminary research of the applicant revealed that Wnt1 regulates the inflammatory activation of microglial cells not only through the Wnt/β-catenin signaling pathways, but also through other signaling pathways. The phosphorylation levels of LKB1、AMPK and the expression level of PGC1-α were upregulated by Wnt1, as it inhibited the the inflammatory activation of BV2 cells induced by Wnt1. Even when the the expression of β-catenin was targeted knocked down, the effection of Wnt1 on LKB1、AMPK and PGC1-α was still significant. The results suggest that Wnt1 may also achieve anti-inflammatory effects through the Wnt/LKB1/PGC1-α signaling pathways. Meanwhile, the anti-inflammatory activation of microglial cells induced by Wnt1 significantly ptrotected myelin sheaths around neurons in white matter from damage in premature rats brain caused by intrauterine infection. The project intends to further analysis the mechanism of the anti-inflammatory activation of microglial cells regulated by Wnt1 through the Wnt/LKB1/PGC1-α signaling pathways, and the protection to the myelin sheaths around neurons in premature rats brain white matter. The project plans to construct a lentiviral vector containing a microglial specific promoter and short hairpin RNA targeted against the LKB1 gene expression, and a siRNA targeted against the SIRT1 gene expression in microglial cells. Then the influences on inflammatory activation of microglial cells and the expression of key protein p-AMPK, SIRT1, etc. in Wnt/LKB1/PGC1-α signaling pathways caused by knocked down expression of LKB1 and SIRT1 is deteced. At last the mechanism of the anti-inflammatory activation of microglial cells regulated by Wnt1 through the Wnt/LKB1/PGC1-α signaling pathways, and the protection to the myelin sheaths around neurons in premature rats brain white matter are verified in animal models. This project will provide a new theoretical basis for the mechanism of Wnt1 in the protection to white matter injury in premature rats induced by intrauterine infection, and fresh ideas for the therapy of white matter injury in premature infants.
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
DOI:10.21037/tp-21-574
发表时间:2022-06
期刊:Translational pediatrics
影响因子:2
作者:
通讯作者:
DOI:--
发表时间:2022
期刊:发育医学电子杂志
影响因子:--
作者:高源;高金枝;徐三清;陈玲
通讯作者:陈玲
DOI:10.3389/fped.2022.913278
发表时间:2022
期刊:FRONTIERS IN PEDIATRICS
影响因子:2.6
作者:Zhao, Caiyan;Chen, Ling;Gao, Jinzhi
通讯作者:Gao, Jinzhi
国内基金
海外基金
