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曲静 研究员

干细胞与衰老研究

联系方式:
Email: qujing@ioz.ac.cn
电话: +86-10-64807768
- 工作人员:曲静,叶燕霞,刘晓倩,白睿军,焦俊妍
- 博士后:初群
- 研究生:刁志清,武泽明,赵宏凯,刘尊鹏,胡慧芳,经瑛,王泽华,毕诗佳,孙国强,郑彦东,李明恒,王敏,刘承宇,张亦欣,王雪宝,张保虎

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  课题组近期研究工作包括:

  1)发展人类精准基因组编辑及成像工具:利用第三代腺病毒载体(HDAdV)介导的同源重组技术,分别矫正了范可尼贫血症、帕金森氏症、儿童早衰症及等疾病遗传突变基因(Nature 2012,Cell Stem Cell 2011,Nature Communications 2014);通过全基因组测序证明了HDAdV和Transcription activator-like effector nuclease(TALEN)两种基因编辑工具的安全性,结合两种工具的优势发展了高效基因矫正工具(telHDAdV,Cell Stem Cell 2014); 发展新型基因组三维成像体系,为探求人类衰老和疾病过程中染色质三维结构及其动态变化提供了有力工具(TTALE,Cell Research 2017)。

  (2)探究干细胞衰老的关键作用通路与干预手段:发现表观遗传改变和基因组不稳定性的互作在干细胞衰老过程中发挥驱动性作用(Science 2015);结合高通量RNA干扰和高内涵生物成像技术,筛选获得了NRF2抗氧化信号通路可以直接调控早衰症细胞衰老这一线索(Cell 2016);揭示SIRT6通过其特异的H3K56去乙酰化酶活性发挥对NRF2靶基因的转录激活作用,从而维持人间充质干细胞的稳态平衡(Cell Research 2016);利用基因编辑技术实现人类干细胞的遗传增强,获得同时抵抗细胞衰老、外界应激及致瘤性转化的优质干细胞(Cell Research 2017)。

  (3)神经系统疾病发生过程中神经及神经干细胞病理改变的分子基础:发现帕金森氏症患者神经干细胞核结构改变的分子基础与病理意义(Nature 2012);发现Cdk5蛋白亚硝基化可引发大脑皮层神经元树突棘丢失(PNAS 2011);建立了神经胶质瘤研究的细胞和动物模型,为神经胶质瘤的起源、发病机理及与衰老的联系等提供了线索与研究平台(Nature Communications 2015)。

  (4)血管系统衰老的关键作用通路与干预手段:建立CADASIL的诱导多能干细胞疾病模型,揭示血管平滑肌退行的分子机理及干预(Protein Cell 2019);通过食蟹猴主动脉弓和冠状动脉血管单细胞测序,发现动脉血管三层细胞随着机体的衰老进程,均呈现长寿基因叉头转录因子FoxO3及其靶基因转录水平的下调;而通过改写FoxO3的两个碱基,成功建立了可同时抵抗细胞衰老和癌变的优质人类血管细胞,为衰老相关心血管疾病的治疗提供了新的策略(Cell Stem Cell 2019)。

  (5)骨关节系统衰老的关键作用通路与干预手段:揭示YAP、CBX4、DGCR8等间充质干细胞的“年轻化”因子,通过抑制细胞衰老从而缓解骨关节炎(PLOS Biology 2019, in press;Cell Reports 2019, in press;Nature Communications 2019, in press)为骨关节炎的基因治疗提供线索。(6)初步开展非人灵长类动物研究:利用CRISPR/Cas9产生首例长寿基因SIRT6全身敲除猴模型,建立灵长类出生前发育迟缓综合征动物研究体系(Nature 2018)。

   



人类基因组编辑及精准成像技术 (Cell 2013, Cell 2012a, Cell 2012b, Cell Stem Cell 2017,Cell Stem Cell 2014, Cell Research 2011)



发现调节灵长类动物血管衰老的核心转录因子及其调控机制(Cell Stem Cell 2019, cover story)



揭示骨关节炎基因治疗的关键分子靶标(Cell Reports 2019)



揭示骨关节炎基因治疗的关键分子靶标 (Plos Biology 2019)



利用单基因治疗实现骨关节炎的干预(Nature Communications 2019)

研究内容与方向:
综合利用人类干细胞和灵长类动物模型,结合新一代组学技术及其他生物学手段,关注人类衰老及相关疾病发生发展过程中,组织特异的生理或病理变化,以及致使这种改变的遗传与环境因素的互作,发现机体或器官退行的标志物,筛选调控器官失稳和促进原位再生的关键基因或候选小分子药物,揭示干细胞衰老的关键调控通路,发展干预人类干细胞衰老乃至器官衰老的有效手段。

 

代表性发表论文:

  1. Li J, Zheng Y, Yan P, Song M, Wang S, Sun L, Liu Z, Ma S, Chan P, Zhou Q, Belmonte JC, Zhang W# , Liu GH# , Tang F# , Qu  J # . (2020) A Single-cell Transcriptomic Atlas of Primate Pancreatic Islet Aging. National Science Review.  2020. DOI: 10.1093/nsr/nwaa127 (# Corresponding author )
  2. Zhang W, Zhang S, Yan P, Ren J, Song M, Li J, Lei J, Pan H, Wang S, Ma X, Ma S, Li H, Sun F, Wan H, Li W, Chan P, Zhou Q, Liu GH# , Tang F# , Qu J # . (2020) A Single-Cell Transcriptomic landscape of Primate Arterial Aging. Nature Communications .  2020.11(1):2202 (# Corresponding author )
  3. Hu H, Ji Q, Song M, Ren J, Liu Z, Wang Z, Liu X, Yan K, Hu J, Wang S# , Zhang W# , Liu GH# , Qu  J # . (2020) ZKSCAN3 counteracts cellular senescence by stabilizing heterochromatin. Nucleic Acids Research.  2020. 19;48(11):6001-6018. (# Corresponding author )
  4. Wang S, Zheng Y, Li J, Yu Y, Zhang W, Song M, Liu Z, Min Z, Hu H, Jing Y, He X, Sun L, Esteban C, Chan P, Qiao J, Zhou Q, Belmonte JC# , Qu  J # , Tang F# , Liu GH# . (2020) Single-Cell Transcriptomic Atlas of Primate Ovarian Aging. Cell.  2020. 180 (3), 585-600.e19. Cover story. (# Corresponding author )
  5. Ma S, Sun S, Geng L, Song M, Wang W, Ye Y, Ji Q, Zou Z, Wang S, He X, Li W, Rodriguez Esteban C, Long X, Guo G, Chan P, Zhou Q, Belmonte JC# , Zhang W# , Qu  J # , Liu GH# . (2020) Caloric Restriction Reprograms the Single-Cell Transcriptional Landscape of Rattus Norvegicus Aging. Cell.  2020.180(5),984-1001.e22 (# Corresponding author )
  6. Lei J, Wang S, Kang W, Chu Q, Liu Z, Sun L, Ji Y, Esteban CR, Yao Y, Belmonte JCI, Chan P, Liu GH# , Zhang W# , Song M# , Qu  J # . (2020) FOXO3-Engineered Human Mesenchymal Progenitor Cells Efficiently Promote Cardiac Repair after Myocardial Infarction. Protein Cell . 2020. DOI: 10.1007/s13238-020-00779-7 (# Corresponding author )
  7. Wang S# , Zheng Y, Li Q, He X, Ren R, Zhang W, Song M, Hu H, Liu F, Sun G, Sun S, Liu Z, Yu Y, Chan P, Zhao GG, Zhou Q, Liu GH# , Tang F#  Qu  J # . (2020) Deciphering primate retinal aging at single-cell resolution. Protein Cell . 2020. DOI: 10.1007/s13238-020-00791-x. (# Corresponding author )
  8. Bi S, Liu Z, Wu Z, Wang Z, Liu X, Wang S, Ren J, Zhang W# , Song M# , Liu GH# , Qu  J # . (2020) SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer. Protein Cell . 2020. 11(7):483-504 (# Corresponding author )
  9. Liang C, Liu Z, Song M, Li W, Wu Z, Wang Z, Wang Q, Wang S, Yan K, Sun L, Hishida T, Cai Y, Izpisua Belmonte JC, Guillen P, Chan P, Zhou Q, Zhang W# , Qu  J # ,  Liu GH# . (2020) Stabilization of Heterochromatin by CLOCK Promotes Stem Cell Rejuvenation and Cartilage Regeneration. Cell Research. 2020. DOI:10.1038/s41422-020-0385-7. (# Corresponding author )
  10. Yan P, Liu Z, Song M, Wu Z, Xu W, Li K, Ji Q, Wang S, Liu X, Yan K, Esteban CR, Ci W, Izpisua Belmonte JC, Xie W, Ren J, Zhang W# , Sun Q# , Qu  J # ,  Liu GH# .(2020) Genome-wide R-loop landscapes during cell differentiation and reprogramming. Cell Reports.  2020. 32(1):107870(# Corresponding author )
  11. Zheng Y, Liu X, Le W, Xie L, Li H, Wen W, Wang S, Ma S, Huang Z, Ye J, Shi W, Ye Y, Liu Z, Song M, Zhang W, Belmonte JCI, Xiao C, Qu  J # , Wang H# , Liu GH# , Su W# . (2020) A human circulating immune cell landscape in aging and COVID-19. Protein Cell . 2020. DOI: 10.1007/s13238-020-00762-2(# Corresponding author )
  12. He X, Memczak S, Qu  J # , Belmonte JC# , Liu GH# . (2020) Single-cell “OMICS” in aging: a young growing field. Nature Metabolism.  2020. 2: 293–302 (# Corresponding author )
  13. Geng L, Liu Z, Wang S, Sun S, Ma S, Liu X, Chan P, Sun L, Song M# , Zhang W# , Liu GH# , Qu  J # . (2019) Low-dose quercetin positively regulates mouse healthspan. Protein Cell . 2019. 10 (10), 770-775 (# Corresponding author )
  14. Zhang X, Liu Z, Liu X, Wang S, Zhang Y, He X, Sun S, Ma S, Shyh-Chang N, Liu F, Wang Q, Wang X, Liu L, Zhang W# , Song M# , Liu GH# , Qu  J # .  (2019) Telomere-Dependent and Telomere-Independent Roles of RAP1 in Regulating Human Stem Cell Homeostasis. Protein Cell . 2019. 10 (9), 649-667 (# Corresponding author )
  15. Yan P, Li Q, Wang L, Lu P, Suzuki K, Liu Z, Lei J, Li W, Ren R, He X, Wang S, Ding J, Chan P, Zhang W, Song M, Belmonte JC, Qu J # , Tang F# , Liu GH# . (2019) FOXO3-engineered human ESC-derived vascular cells promote vascular protection and regeneration. Cell Stem Cell.  2019. 24(3), 447-461 (cover story) (# Corresponding author )
  16. Deng L, Ren R, Liu Z, Song M, Li J, Wu Z, Ren X, Fu L, Li W, Zhang W, Guillen P, Belmonte J, Chan P, Qu  J # , Liu GH# . (2019) Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis. Nature Communications.  2019.10(1):3329. (# Corresponding author )
  17. Fu L, Hu Y, Song M, Liu Z, Zhang W, Yu FX, Wu J, Wang S, Belmonte JC, Chan P, Qu J # , Tang F# , Liu GH# . (2019) Upregulation of FOXD1 by YAP alleviates senescence and osteoarthritis. PLoS Biology.  2019. 17(4):e3000201 (# Corresponding author )
  18. Ren X, Hu B, Song M, Ding Z, Dang Y, Liu Z, Zhang W, Ji Q, Ren R, Ding J, Chan P, Jiang C, Ye K, Qu J # , Tang F# , Liu GH# . (2019) Maintenance of nucleolar homeostasis by CBX4 alleviates senescence and osteoarthritis. Cell Reports . 2019. 26(13):3643-3656. (# Corresponding author )
  19. Zhang W, Song M, Qu J #  Liu GH# . Epigenetic Modifications in Cardiovascular Aging and Diseases. Circ ulation  Res earch .  2018. 123(7):773-786. (# Corresponding author )
  20. Ren R, Deng L, Xue Y, Suzuki K, Zhang W, Yu Y, Wu J, Sun L, Gong X, Luan H, Yang F, Ju Z, Ren X, Wang S, Tang H, Geng L, Zhang W, Li J, Qiao J, Xu T# , Qu J # , Liu GH# . (2017) Visualization of aging-associated chromatin alterations with an engineered TALE system. Cell Res earch.  2017. 27(4):483-504 (# Corresponding author )