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曲静 研究员

干细胞与衰老研究

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- 工作人员:曲静,叶燕霞,刘晓倩,白睿军
- 博士后:鲍文蕾,张晓倩,初群
- 研究生:刁志清,武泽明,张钘,赵宏凯,刘尊鹏,胡慧芳,王泽华,毕诗佳

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  课题组近期研究工作包括:

  (1)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)。

  (2)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,分别矫正了帕金森氏症、儿童早衰症及范可尼贫血症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 2011);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)。

  (3)人类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)。

   



SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. (Cell Res. 2016 Jan 15. doi: 10.1038/cr.2016.4.)



Strategy of genetically enhancement: activating NRF2 in a stable and controllable manner by single-nucleotide variation (A245G). (Cell Res. 2017. Jan 31. doi: 10.1038/cr.2017.18.)



NRF2 defect is a key contributor to premature aging in Hutchinson-Gilford progeria syndrome. (Cell. 2016. 165,1-14.)



A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. ( Science. 2015 Apr 30. pii: aaa1356.)

研究内容与方向:
  本课题组关注人类衰老及衰老相关疾病发生发展过程中,组织特异性干细胞的生理或病理变化,以及致使这种改变的遗传因素与环境因素的互作关系。通过建立人干细胞研究体系,逐一梳理并阐明干细胞增龄性改变的标志物,发掘介导干细胞衰老的关键作用通路,并据此发展有效减缓人类干细胞衰老的干预手段。综合利用人类早衰症和非人灵长类动物模型,结合新一代组学技术及其他生物学手段,研究人类器官退行和组织特异细胞稳态改变的分子信号网络,绘制增龄伴随的遗传和表观遗传变化图谱,发现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。

 

代表性发表论文:

  1. Zhang W1, Wan H1, Feng G1, Qu J1, Wang J, Jing Y, Ren R, Liu Z, Zhang L, Chen Z, Wang S, Zhao Y, Wang Z, Yuan Y, Zhou Q, Li W, Liu GH, Hu B.SIRT6 deficiency results in developmental retardation in cynomolgus monkeys. . 2018 in press. doi:10.1038/s41586-018-0437-z. (1equal contribution).
  2. Zhang W, Song M, Qu J*, Liu GH*. Epigenetic Modifications in Cardiovascular Aging and Diseases.Circ Res. 2018 in press. (*Corresponding author)
  3. Yang J, Li J, Suzuki K, Liu X, Wu J, Zhang W, Ren R, Zhang W, Chan P, Izpisua Belmonte JC, Qu J*, Tang F*, Liu GH*. Genetic enhancement in cultured human adult stem cells conferred by a single nucleotide recoding. Cell Res. 2017 Jul 7. doi: 10.1038/cr.2017.86.(*Corresponding author)
  4. 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*. Visualization of aging-associated chromatin alterations with an engineered TALE system. Cell Res. 2017. Jan 31. doi: 10.1038/cr.2017.18. (*Corresponding author)
  5. Kubben N, Zhang W#, Wang L, Voss T, Yang J, Qu J#, Liu GH*, Misteli T* Repression of the antioxidant NRF2 pathway in premature aging. Cell. 2016. 165,1-14. Highlighted by Cell, doi: http://dx.doi.org/10.1016/j. cell.2016.05.061 (#Co-senior author)
  6. Suzuki K, Tsunekawa Y, Hernandez-Benitez R, Wu J, Zhu J, Kim EJ, Hatanaka F1, Yamamoto M, Araoka T, LiZ, Kurita M, Hishida T, Li M, Aizawa E, Guo S, Chen S, Goebl A, Soligalla RD, Qu J, Jiang T, Fu X, Jafari M, Esteban CR, Berggren WT, Lajara J, Nu?ez-Delicado E, Guillen P, Campistol JM, Matsuzaki F, Liu GH, Magistretti P, Zhang K, Callaway EM, Zhang K, Belmonte JC. In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration. Nature. 2016. 540(7631):144-149. doi: 10.1038/nature20565.
  7. Pan H, Guan D, Liu X, Li J, Wang L, Wu J, Zhou J, Zhang W, Ren R, Zhang W, Li Y, Yang J, Hao Y, Yuan T, Yuan G, Wang H, Ju Z, Mao Z, Li J, Qu J*, Tang F*, Liu GH*. SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Cell Res. 2016 Jan 15. doi: 10.1038/cr.2016.4. (*Corresponding author)
  8. Zhang W1, Li J1, Suzuki K1, Qu J1, Wang P, Zhou J, Liu X, Ren R, Xu X, Ocampo A, Yuan T, Yang J, Li Y, Shi L, Guan D, Pan H, Duan S, Ding Z, Li M, Yi F, Bai R, Wang Y, Chen C, Yang F, Li X, Wang Z, Aizawa E, Goebl A, Soligalla RD, Reddy P, Esteban CR, Tang F, Liu GH, Belmonte JC. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science. 2015 Apr 30. pii: aaa1356. (1equal contribution)
  9. Suzuki K1, Yu C1, Qu J1, Li M1, Yao X, Yuan T, Goebl A, Tang S, Ren R, Aizawa E, Zhang F, Xu X, Soligalla R, Chen F, Kim J, Kim NY, Liao HK, Benner C, Esteban CR, Jin Y, Liu GH*, Li Y* , Belmonte JC*.Targeted gene correction in human disease-specific induced pluripotent stem cells minimally impacts whole-genome mutational load. Cell Stem Cell. 2014. 2014; 15, 31–36. (1equal contribution)
  10. Liu GH1, Qu J1, Suzuki K1, Nivet E, Li M, Montserrat N, Yi F, Xu X, Ruiz S, Zhang W, Ren B, Wagner U, Kim A, Li Y, Goebl A, Kim J, Soligalla R, Dubova I, Thompson J, Yates JIII, Esteban C, Sancho-Martinez I, Belmonte JC. Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature, 2012,491(7425):603-7. Highlighted by Nature Reviews Neurology (Nature Reviews Neurology | doi:10.1038/nrneurol.2012.230) (1equal contribution)
  11. Liu GH1, Suzuki K1, Qu J1, Sancho-Martinez I, Yi F, Li M, Kumar S, Nivet E, Kim J,  Soligalla RD, Dubova I, Goebl A, Plongthongkum N, Fung HL, Zhang K, Loring J, Laurent L, and Belmonte JC. Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs. Cell Stem Cell. 2011, 8(6):688-94. Highlighted by Nature (Nature 474, 8. doi:10.1038/474008c) and Cell Stem Cell (Cell Stem Cell 9, 2: 93-94) (1equal contribution).
  12. Qu J1, Nakamura T1, Cao G, Mckercher S, Lipton S. S-Nitrosylation Activates Cdk5 and Contributes to Synaptic Spine Loss Induced by β-Amyloid Peptide. Proceedings of the National Academy of Sciences. 2011, 108(34):14330-5. doi: 10.1073/pnas.1105172108 (1equal contribution).
  13. Liu GH, Barkho BZ, Ruiz S, Diep D, Qu J, Yang SL, Panopoulos AD, Suzuki K, Kurian L, Walsh C, Thompson J, Boue S, Fung HL, Sancho-Martinez I, Zhang K, Iii JY, Belmonte JC. Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature. 2011; 14;472: 221-5.doi: 10.1038/nature09879.