CHMP2A/VPS4介导自噬溶酶体关闭异常在缺血缺氧性脑病中的作用及机制

批准号:
81974284
项目类别:
面上项目
资助金额:
55.0 万元
负责人:
崔德荣
依托单位:
学科分类:
心肺复苏
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
崔德荣
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中文摘要
新生儿缺血缺氧性脑病(HIE)严重威胁新生儿健康,但发病机制不明。申请人前期研究显示心脏骤停-心肺复苏(CA-CPR)诱导的新生动物HIE模型在处理6-24h内出现大脑自噬流受损,并发现自噬流受损与CHMP2A/VPS4介导的自噬溶酶体关闭异常密切相关。故提出研究假说:在CA-CPR 诱导的HIE中,CHMP2A在损伤神经元中表达降低,抑制VPS4介导的自噬溶酶体关闭及成熟,导致自噬流受损和HIE发生。本项目拟通过免疫电镜等技术,在CA-CPR 诱导的HIE模型中首先阐明CHMP2A/VPS4介导的自噬溶酶体关闭及成熟的分子机制,其次验证该过程是否会受到Beclin-1调控,最后在体水平探索CHMP2A/VPS4基因干预是否能恢复受损自噬流,缓解神经元损伤。本项目将揭示CHMP2A/VPS4介导自噬溶酶体的关闭及成熟在HIE中的机制,将为HIE防治及药物开发提供科学依据,具有重要临床意义。
英文摘要
Neonatal hypoxic ischemic encephalopathy (HIE) is a serious threat to the physical health of newborns, but its pathogenesis is still unclear. The previous studies have shown that the autophagic flux was impaired within 6 to 24 h after restoration of spontaneous circulation (ROSC) in the brain of neonatal animal HIE model induced by cardiac arrest - cardiopulmonary resuscitation (CA - CPR), which is consistent with the second and early third phases in clinical patients suffered from HIE. Moreover, through series of preliminary experiments, we focused on CHMP2A-mediated autolysosome closure and maturation. Therefore, a hypothesis is proposed: in the CA-CPR induced neonatal HIE mice model, the expression of CHMP2A is decreased in injured neurons, which leads to VPS4-mediated impairment of autolysosome closure and maturation. This project intends to investigate the mechanism of CHMP2A/VPS4-mediated autolysosome closure and maturation in CA-CPR-induced HIE model by using immunoelectron microscopy and other molecular biology technology. Further we will verify whether the process is regulated by Beclin-1 and explore whether CHMP2A and VPS4 gene intervention can restore autophagic flux and alleviate neuronal damage in vivo. Through this project, we will unveil the mechanism of CHMP2A/VPS4-mediated autolysosome closure and maturation in CA-CPR-induced HIE. It will provide a scientific basis for HIE prevention and drug development, which has important clinical significance.
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DOI:10.16557/j.cnki.1000-7547.2022.02.004
发表时间:2022
期刊:神经解剖学杂志
影响因子:--
作者:邵蓉娇;崔德荣
通讯作者:崔德荣
Increased PINK1/Parkin-mediated mitophagy explains the improved brain protective effects of slow rewarming following hypothermia after cardiac arrest in rats
PINK1/Parkin 介导的线粒体自噬增加解释了大鼠心脏骤停后体温过低后缓慢复温对大脑保护作用的改善
DOI:10.1016/j.expneurol.2020.113326
发表时间:2020-08-01
期刊:EXPERIMENTAL NEUROLOGY
影响因子:5.3
作者:Hu, Yue;Sun, Dawei;Cui, Derong
通讯作者:Cui, Derong
Effects of the Incidence Density of Fever (IDF) on Patients Resuscitated From In-Hospital Cardiac Arrest: A Mediation Analysis
发热发生密度 (IDF) 对院内心脏骤停复苏患者的影响:中介分析
DOI:10.3389/fmed.2020.00086
发表时间:2020-03-25
期刊:FRONTIERS IN MEDICINE
影响因子:3.9
作者:Hu,Yue;Guo,Yong;Cui,Derong
通讯作者:Cui,Derong
DOI:10.1186/s12974-021-02307-8
发表时间:2021-11-05
期刊:Journal of neuroinflammation
影响因子:9.3
作者:Shao R;Wang X;Xu T;Xia Y;Cui D
通讯作者:Cui D
DOI:10.3969/j.issn.1674-8115.2020.11.003
发表时间:2020
期刊:上海交通大学学报. 医学版
影响因子:--
作者:李艺;胡月;孙大伟;崔德荣
通讯作者:崔德荣
自噬流/炎症小体失衡在新生儿缺血缺氧性脑病中的作用机制
- 批准号:82372205
- 项目类别:面上项目
- 资助金额:49.00万元
- 批准年份:2023
- 负责人:崔德荣
- 依托单位:
心跳骤停-心肺复苏后大脑自噬流受损触发神经细胞死亡的作用及机制
- 批准号:81671879
- 项目类别:面上项目
- 资助金额:58.0万元
- 批准年份:2016
- 负责人:崔德荣
- 依托单位:
国内基金
海外基金
