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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:张晓倩,初群
- 研究生:刁志清,武泽明,赵宏凯,刘尊鹏,胡慧芳,王泽华,毕诗佳,郑彦东,李明恒,王敏

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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:
  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,发现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. 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*. FOXO3-engineered human ESC-derived vascular cells promote vascular protection and regeneration. Cell Stem Cell. 2019. 24(3), 447-461 (cover story) (*Corresponding author)
  2. 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*. Upregulation of FOXD1 by YAP alleviates senescence and osteoarthritis. PLoS Biology. 2019. 17(4):e3000201 (*Corresponding author)
  3. 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*. Telomere-Dependent and Telomere-Independent Roles of RAP1 in Regulating Human Stem Cell Homeostasis. Protein Cell. 2019. DOI: 10.1007/s13238-019-0610-7 (*Corresponding author)
  4. 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. Nature. 2018. 560(7720):661-665. (1equal contribution)
  5. Zhang W, Song M, Qu J*, Liu GH*. Epigenetic Modifications in Cardiovascular Aging and Diseases. Circ Res. 2018. 123(7):773-786. (*Corresponding author)
  6. Wang P, Liu Z, Zhang X, Li J, Sun L, Ju Z, Li J, Chan P, Liu GH*, Zhang W*, Song M*, Qu J*. CRISPR/Cas9-mediated Gene Knockout Reveals a Guardian Role of NF-κB/RelA in Maintaining the Homeostasis of Human Vascular Cells. Protein Cell. 2018. 9(11):945-965. (*Corresponding author)
  7. 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 Sep;27(9):1178-1181. doi: 10.1038/cr.2017.86. (*Corresponding author)
  8. 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 Apr;27(4):483-504. doi: 10.1038/cr.2017.18. (*Corresponding author)
  9. 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 Jun 2;165(6):1361-1374. doi: 10.1016/j.cell.2016.05.017. Highlighted by Cell (doi: http://dx.doi.org/10.1016/j.cell.2016.05.061). (#Co-senior author)
  10. 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 Feb;26(2):190-205. doi: 10.1038/cr.2016.4. (*Corresponding author)
  11. Duan S, Yuan G, Liu X, Ren R, Li J, Zhang W, Wu J, Xu X, Fu L, Li Y, Yang J, Zhang W, Bai R, Yi F, Suzuki K, Gao H, Esteban CR, Zhang C, Belmonte JC, Chen Z, Wang X, Jiang T, Qu J*, Tang F*, Liu GH*. PTEN deficiency reprograms human neuralstem cells towards a glioblastoma stem cell-like phenotype. Nat Commun. 2015 Dec 3;6:10068. doi: 10.1038/ncomms10068. (*Corresponding author)
  12. 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 Jun 5;348(6239):1160-3. doi: 10.1126/science.aaa1356. (1equal contribution)
  13. Ding Z, Sui L, Ren R, Liu Y, Xu X, Fu L, Bai R, Yuan T, Hao Y, Zhang W, Pan H, Liu W, Yu H, Esteban C, Yu X, Yang Z, Li J, Wang X, Belmonte JC, Liu GH*, Yi F*, Qu J*. A widely adaptable approach to generate integration-free iPSCs from non-invasively acquired human somatic cells. Protein Cell. 2015 May;6(5):386-9. doi: 10.1007/s13238-014-0117-1. (*Corresponding author)
  14. 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; 15, 31–36. doi:https://doi.org/10.1016/j.stem. 2014.06.016. (1equal contribution)
  15. Yang J1, Cai N1, Yi F1, Liu GH*, Qu J*, Belmonte JC*. Gating pluripotency via nuclear pores. Trends Mol Med. 2014. Jan; 20(1):1-7. doi: 10.1016/j.molmed.2013.10.003. (*Corresponding author)
  16. Li M1, Liu W1, Yuan T, Bai R, Liu GH*, Zhang W*, Qu J*. DNA methylome: Unveiling your biological age. Protein Cell. 2013 Oct;4(10):723-5. doi: 10.1007/s13238-013-3913-0. (*Corresponding author)
  17. 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 Nov 22;491(7425):603-7. doi: 10.1038/nature11557. (1equal contribution) .
  18. 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 Jun 3;8(6):688-94. doi: 10.1016/j.stem.2011.04.019. (1equal contribution).