新跨膜因子Angel Face调控质膜向自噬体膜转化的机理研究
结题报告
批准号:
92054109
项目类别:
重大研究计划
资助金额:
82.0 万元
负责人:
李周华
依托单位:
学科分类:
细胞衰老、死亡及自噬
结题年份:
2023
批准年份:
2020
项目状态:
已结题
项目参与者:
李周华
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
客服二维码
微信扫码咨询
中文摘要
自噬在细胞稳态维持和个体发育过程中发挥重要作用,自噬异常会导致退行性疾病和癌症等疾病。但自噬体发生过程中质膜向自噬体膜转化的详细机制仍不清楚。我们已发表的研究表明自噬可以有效抑制果蝇肠道和肾脏肿瘤;通过筛选,我们发现一个新的保守跨膜因子Angel Face。我们的前期研究发现其在多种细胞缺失后均导致强烈自噬,自噬流加快和溶酶体改变;自噬发生是由mTOR信号被抑制导致的;通过质膜标记,我们还发现质膜很可能通过内吞转化为自噬体膜;且AnFa与ATG9共定位于质膜上(请见研究基础)。因此,本课题拟详细研究AnFa调控自噬发生的分子机制,并通过生化、细胞和遗传等方法,阐明其调控质膜向自噬体膜转化和质膜与自噬体膜互作的分子机制,最后通过人源细胞模型确定AnFa调控自噬发生和质膜向自噬体膜转化的保守性。该研究将加深我们对自噬体膜来源及调控分子机制和质膜与自噬体膜互作的理解,进一步推进自噬领域的研究。
英文摘要
Autophagy (macroautophagy) plays a fundamental role in the cellular, tissue homeostasis, and organism development. Dysfunctions of autophagy are often implicated in various diseases including degenerative diseases and cancer. However, the molecular mechanism of the contribution of plasma membrane to autophagosome membrane still remains elusive. Our published data showed that induction of autophagy could effectively inhibit the formation of intestinal and renal tumors in adult Drosophila (Ma et al., 2016). From a genome-wide RNAi screen, we found that upon knock down of AnFa (Angel Face), a novel gene encoding a conserved transmembrane protein, autophagy was strongly induced in multiple cell types due to the inhibition of mTOR signaling, restoring mTOR signaling can suppress autophagy in AnFa knockdown cells, autophagic flux was increased and the morphology of lysosomes was changed in the AnFa knockdown cells. Most interestingly, we found that plasma membrane was converted to autophagosome/autolysosome membrane by membrane labeling, and plasma membrane internalization is likely required in this process. AnFa and ATG9 are co-localized on the plasma membrane (please refer to the "results" part). Based on these findings, we will investigate the underlying molecular mechanisms that AnFa negatively regulates autophagosome biogenesis; and elucidate its molecular mechanism in the contribution of plasma membrane to autophagosome membrane and the interaction between plasma membrane and autophagosome membrane, through the combination of technologies of biochemistry, cell biology, and genetics etc; and study whether its functions are evolutionarily conserved in mammalian cells. As Drosophila and mammals share extensive similarities in autophagy, this study will deepen our understandings of the original membrane sources of autophagosome membrane, the underlying molecular mechanisms of the contribution of plasma membrane to autophagosome membrane, and the interaction between plasma membrane and autophagosome membrane, having potential clinical importance.
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:10.1016/j.stemcr.2022.03.010
发表时间:2022-05-10
期刊:STEM CELL REPORTS
影响因子:5.9
作者:Zhao, Hang;Ren, Xuejing;Kong, Ruiyan;Shi, Lin;Li, Zhengran;Wang, Runqi;Ma, Rui;Zhao, Huiqing;Liu, Fuli;Chang, Henry C.;Chen, Chun-Hong;Li, Zhouhua
通讯作者:Li, Zhouhua
DOI:10.1242/dev.201958
发表时间:2023-12-01
期刊:DEVELOPMENT
影响因子:4.6
作者:Shi,Lin;Ma,Hubing;Li,Zhouhua
通讯作者:Li,Zhouhua
DOI:10.1016/j.jgg.2021.08.017
发表时间:2022-03-28
期刊:JOURNAL OF GENETICS AND GENOMICS
影响因子:5.9
作者:Liu, Fuli;Zhao, Hang;Li, Zhouhua
通讯作者:Li, Zhouhua
DOI:10.1016/j.stemcr.2022.07.014
发表时间:2022-09-13
期刊:STEM CELL REPORTS
影响因子:5.9
作者:Zhao, Hang;Li, Zhengran;Kong, Ruiyan;Shi, Lin;Ma, Rui;Ren, Xuejing;Li, Zhouhua
通讯作者:Li, Zhouhua
DOI:10.1016/j.ydbio.2021.04.008
发表时间:2021-04
期刊:Developmental biology
影响因子:2.7
作者:Hang Zhao;Lin Shi;Ruiyan Kong;Zhengran Li;Fuli Liu;Huiqing Zhao;Zhouhua Li
通讯作者:Hang Zhao;Lin Shi;Ruiyan Kong;Zhengran Li;Fuli Liu;Huiqing Zhao;Zhouhua Li
m6A修饰调控肠道干细胞增殖和肠道稳态的分子机制研究
  • 批准号:
    32370841
  • 项目类别:
    面上项目
  • 资助金额:
    50万元
  • 批准年份:
    2023
  • 负责人:
    李周华
  • 依托单位:
内质网膜蛋白复合体调控肠道干细胞增殖和肠道稳态的分子机制研究
  • 批准号:
    31972893
  • 项目类别:
    面上项目
  • 资助金额:
    57.0万元
  • 批准年份:
    2019
  • 负责人:
    李周华
  • 依托单位:
抗增殖蛋白Prohibitin调节果蝇中肠稳态的机理研究
  • 批准号:
    31471384
  • 项目类别:
    面上项目
  • 资助金额:
    85.0万元
  • 批准年份:
    2014
  • 负责人:
    李周华
  • 依托单位:
气管来源的BMP信号维持果蝇中肠稳态的机理研究
  • 批准号:
    31271582
  • 项目类别:
    面上项目
  • 资助金额:
    82.0万元
  • 批准年份:
    2012
  • 负责人:
    李周华
  • 依托单位:
国内基金
海外基金