项目来源
国家重点研发计划(NKRD)
项目主持人
邱小波
项目受资助机构
中国科学院分子细胞科学卓越创新中心
立项年度
2019
立项时间
未公开
项目编号
2019YFA0802103
研究期限
未知 / 未知
项目级别
国家级
受资助金额
506.00万元
学科
发育编程及其代谢调节
学科代码
未公开
基金类别
未公开
关键词
信号转导 ; 自闭症 ; 全反式维甲酸 ; 神经可塑性 ; m6A修饰 ; Signaling transduction ; Autism Spectrum Disorder ; All-trans Retinoic Acid ; Neural plasticity ; m6A modification
参与者
胡荣贵；伊丽米热
参与机构
云南大学
项目标书摘要：我们发现E3泛素连接酶GXB1可以与视黄酸降解代谢酶CYP26A1相互作用，并且泛素化修饰它，在不影响蛋白水平的情况下抑制了它的活性。随后我们构建了GXB1基因敲除的小鼠模型，发现GXB1缺失的小鼠表现出自闭症样的行为，可能是由于视黄酸降解加快导致的。而向其回补视黄酸后，可以缓解自闭症样的行为，进一步说明GXB1基因敲除可能是视黄酸代谢异常导致的。此外，我们通过对GXB1敲除小鼠进行RNA-seq分析，发现GXB1缺失后会引起神经细胞形态、突触的功能等生命活动异常，提示GXB1敲除之后，减少了对CYP26A1的泛素化修饰，使其活性增加，加速视黄酸的降解，视黄酸水平降低影响了正常的神经电活动，最终导致自闭症的发生。这些成果有助于更加深入的理解自闭症发病机制，并且提供了“补充视黄酸“”这个治疗自闭症的新思路。另外，我们还明确了m6A与果蝇早期胚胎的母源mRNA的降解的相关性，发现FMR1优先结合m6A修饰的RNA,通过相分离影响FMR1的RNA颗粒大小和活性，调节早期胚胎母源mRNA的降解。这有助于我们深入理解果蝇早期胚胎发育过程。
Application Abstract: We have basically accomplished these goals,and published 6 scientific papers(2 of them acknowledged this project at the first place).We found out that E3 ubiquitin ligase GXB1 interacts with and ubiquities CYP26A1,the metabolic enzyme of retinoic acid,results in a decrease in its metabolic activity without changing the protein levels.Next,we discovered that the autistic-like behaviors in GXB1 knockout mice might result from increasing degradation of retinoic acid(RA),which could be rescued by supplement of RA.The results of RNA-seq also revealed that neural network and synaptic functions were affected by GXB knockout.These findings suggested that knockout of GXB1 decreased the ubiquitination of CYP26A1,increased its metabolic activity and accelerated the degradation of RA.The normal neural activity was impaired,therefore induced autistic-like behaviors in mice.Our results should help people understand the pathogenesis of autism and provide a new strategy to treat autism,supplementation of retinoic acid._x000D_Furthermore,we revealed the association between m6A modification and mRNA degradation during early embryonic development.We found that FMR1 protein bound m6A modified mRNA in prior and could influence the FMR1-RNA particle by phase-phase separation,then regulate the degradation of mRNA in early embryos.These findings should help us to better understand the early embryonic development of fruit fly.
项目受资助省
上海市
