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  范祖森 博士 研究员 博士生导师 

  国家“杰出青年基金”、国家“新世纪百千万人才工程”、中科院“百人计划”获得者

  中科院生物物理所,中科院感染与免疫重点实验室副主任,创新课题组组长

  研究方向:

  1、 天然免疫新亚群发现与抗感染机制

  2、 LncRNA与免疫调控

  3、 肿瘤干细胞与肿瘤免疫治疗

  电子邮件(E-mail) fanz@moon.ibp.ac.cn,电话(Tel) 010-64888457

  英文版个人网页

  简历 & 研究组工作摘要

  范祖森,二级研究员,现任中科院感染与免疫重点实验室副主任,国科大微免教研室副主任,中国科学院特聘核心骨干研究员,国科大岗位教授(A类)。范祖森1998年获上海交通大学医学院免疫学博士学位,随后到哈佛大学医学院从事博士后研究,于2003年晋升为哈佛大学讲师。2004年作为中国科学院“百人计划”研究员回到生物物理所工作,2005年获“杰出青年”基金资助,2006年入选“新世纪百千万人才工程”国家级人才。2010年享受“国务院特殊津贴”专家。2014年获得谈家桢生命科学创新奖,2016年评为中科院优秀研究生导师。课题组长期从事天然免疫抗感染应答调控、肿瘤干细胞和肿瘤免疫治疗等研究,在天然免疫细胞新亚群发现、天然免疫抗感染识别机制、肿瘤干细胞自我更新机制等方面,取得了一系列有国际影响力的原创性成果。以第一及通讯作者在Cell(2篇)、Nat Immunol(5篇)、Immunity(2篇)、Cell Stem Cell(2篇)、JEM(3篇)、JCI、NSMB、Nat Commun(8篇)、 EMBO J(2篇)、Blood等国际权威学术期刊发表SCI高水平研究论文70余篇,研究处于国际前沿。课题组经过多年的研究积累业已形成优秀的免疫学研究平台和优良的科研文化氛围,在天然免疫抗感染应答与肿瘤免疫领域培养出一支优秀的科研团队。已培养了30余位博士毕业生和近10位博士后,10余人获得中科院院长特别奖、优秀奖及优秀博士论文,有近10人晋升为教授岗位(包括北大、清华教授),3人获得中组部“青年千人”计划,1人获得基金委“优青”等。

  课题组主要研究方向如下:

  本课题组从事天然免疫抗感染应答调控、肿瘤干细胞和肿瘤免疫治疗研究。主要研究内容分为天然免疫细胞新亚群发现与抗感染机制、LncRNA与免疫调控、以及肿瘤干细胞与肿瘤免疫治疗等三个方向。

  一、 天然免疫细胞新亚群发现与抗感染机制

  我们发现鉴定了数个天然免疫识别受体,揭示了其抗感染免疫识别应答作用(Nat Immunol, 2015、2016、2018; Cell Stem Cell,2013);揭示了免疫细胞颗粒酶抗感染/抗肿瘤的作用及结构基础(Cell,2003;Nat Immunol, 2003;Mol Cell Biol, 2002;Blood, 2006;Cell Death Differ, 2006、2007、2009、2012a、2012b、2013;JImmunol,2006、2009a、2009b、2009c、2010、2012a、2012b、2013、2015)。发现鉴定了数个天然免疫细胞的新亚群,发现新亚群NKB细胞通过分泌IL-18活化NK和ILC1细胞,参与抗感染免疫应答(Immunity,2016、2017)。还发现一群新的ILC调节细胞亚群(ILCreg),通过分泌IL-10参与调控抗感染免疫应答(Cell,2017)。我们将利用单细胞测序等新技术,继续发现鉴定天然免疫细胞新亚群及其功能。我们将深入探索新亚群ILCreg的谱系建立机制,探究调控ILC细胞亚型转变的调节机制。探究生理及病理诱导ILC细胞亚型转变的调控作用和分子机制,探明ILC亚型相互转变对炎症诱发与转归的调控作用。揭示天然免疫抗感染应答调控及可塑性机制,以期为感染性疾病的防治提供理论依据。

  二、 LncRNA与免疫调控

  长非编码核酸(lncRNA)的发现和功能机制是生物医学领域的研究前沿。我们近期发现,环状RNA cia-cGAS在免疫前体HSC细胞核内结合DNA识别受体cGAS抑制其活化,阻断I型干扰素的产生,从而维持HSC的稳态(Immunity, 2018)。还发现lncKdm2b通过招募NURF复合物活化转录因子Zfp292的表达,维持ILC3细胞的扩增和免疫应答效应(Nat Immunol,2017; EMBO J, 2018)。我们将利用RNA-seq、高通量筛选等技术,鉴定新的lncRNA,探究lncRNA对ILC细胞的谱系建立、激活应答、免疫效应等调控作用,揭示其发挥功能的分子机制,阐释lncRNA与免疫疾病的致病关系,为疾病诊断和干预提供新靶点和新策略。

  三、 肿瘤干细胞与肿瘤免疫治疗

  肿瘤干细胞具有超强的致瘤能力和自我更新潜能,靶向肿瘤干细胞是肿瘤治愈的新希望。我们鉴定了肝癌组织中共表达CD13和CD133的少量肿瘤干细胞(Cell Stem Cell,2015),揭示了数个重要基因参与调控肝癌干细胞的自我更新机制(JCI,2015;Nature Commun,2015)。并率先鉴定发现多个新lncRNA对肝癌干细胞具有重要的调控作用(Cell Stem Cell,2015;NSMB,2016;Nature Commun,2016;Cancer Res,2017)。课题组还鉴定了识别膀胱癌干细胞的新靶标抗体(Clin Cancer Res,2014),揭示了新靶标抗体干预膀胱癌生长的机制(Cancer Res,2016)。基于新靶标抗体,研发了膀胱癌的靶向抗体药物和早期诊断试剂盒。我们将继续鉴定发现新的肿瘤干细胞标志物,研究肿瘤干细胞的自我更新机制,研发靶向干细胞的抗肿瘤药物,以期实现有效的肿瘤免疫治疗,普惠肿瘤患者。

  代表性研究论文:

  2018

  1. Xia P, Wang S, Xiong Z, Zhu X, Ye B, Du Y, Meng S, Qu Y, Liu J, Gao G, Tian Y*, Fan Z*. The ER membrane adaptor ERAdP senses the bacterial second messenger c-di-AMP and initiates anti-bacterial immunity. Nat Immunol. 2018;19(2):141-150.

  2. Xia P, Wang S, Ye B, Du Y, Li C, Xiong Z, Qu Y, Fan Z*. Circular RNA cia-cGAS protects dormant hematopoietic stem cells from DNA sensor cGAS-mediated exhaustion. Immunity. 2018 (in press)

  3. Ye B, Liu B, Hao  L, Zhu X, Yang  L, Wang S, Xia P, Du Y, Meng S, Huang G, Qin X, Wang Y, Yan X, Li C, Hao J, Zhu P, He L, Tian* Y, Fan Z*. Klf4 glutamylation is required for cell reprogramming and early embryonic development in mice. Nat Commun. 2018 (accepted)

  4. Ye B, Liu B, Yang L, Zhu X, Zhang D, Wu W, Zhu P, Wang Y, Wang S, Xia P,  Du Y, Meng S, Huang G, Wu J, Chen R*, Tian Y*, Fan Z*. LncKdm2b controlsself-renewal of embryonic stem cells viaactivation of transcription factor Zbtb3. EMBO J. 2018 (accepted)

  2017

  5. Wang S*, Xia P, Chen Y, Qu Y, Xiong Z, Ye B, Du Y, Tian Y, Yin Z, Xu Z, Fan Z*. Regulatory Innate Lymphoid Cells Control Innate Intestinal Inflammation. Cell. 2017;171(1):201-216.

  6. Liu B, Ye B, Yang L, Zhu X, Huang G, Zhu P, Du Y, Wu J, Qin X, Chen R*, Tian Y*, Fan Z*. Long non-coding RNA lncKdm2b is required for the maintenance of group 3 innate lymphoid cells by initiating Zfp292 expression. Nat Immunol. 2017;18(5):499-508.

  7. Wang S*, Xia P, Fan Z*. Natural-Killer-like B Cells Function as a Separate Subset of Innate B Cells. Immunity. 2017; 47(2):201-202.

  8. Xia P, Liu J, Wang S, Ye B, Du Y, Xiong Z, Han ZG, Tong L, Fan Z*. WASH maintains NKp46+ ILC3 cells by promoting AHR expression. Nat Commun. 2017;8:15685.

  9. Liu B, Ye B, Zhu X, Huang G, Yang L, Zhu P, Du Y, Wu J, Meng S, Tian Y*, Fan Z*. IL-7Rα glutamylation and activation of transcription factor Sall3 promote group 3 ILC development. Nat Commun. 2017;8(1):231.

  10. Ye B, Liu B, Yang L, Huang G, Hao L, Xia P, Wang S, Du Y, Qin X, Zhu P, Wu J, Sakaguchi N, Zhang J, Fan Z*. Suppression of SRCAP chromatin remodelling complex and restriction of lymphoid lineage commitment by Pcid2. Nat Commun. 2017; 8(1): 1518.

  11. Yang Z#, Li C#, Fan Z#, Liu H, Zhang X, Cai Z, Xu L, Luo J, Huang Y, He L, Liu C, Wu S. Single-cell Sequencing Reveals Variants in ARID1A, GPRC5A and MLL2 Driving Self-renewal of Human Bladder Cancer Stem Cells. Eur Urol. 2017;71(1):8-12.

  12. Yan X, Zhang D, Wu W, Wu S, Qian J, Hao Y, Yan F, Zhu P, Wu J, Huang G, Huang Y, Luo J, Liu X, Liu B, Chen X, Du Y, Chen R*, Fan Z*. Mesenchymal stem cells promote hepatocarcinogenesis via lncRNA-MUF interaction with ANXA2 and miR-34a. Cancer Res. 2017; 77(23):6704-6716.

  2016

  13. Xia P, Ye B, Wang S, Zhu X, Du Y, Xiong Z, Tian Y*, Fan Z*. Glutamylation of the DNA sensor cGAS regulates its binding and synthase activity in antiviral immunity. Nat Immunol. 2016;17(4):369-78.

  14. Wang S, Xia P, Chen Y, Huang G, Xiong Z, Liu J, Li C, Ye B, Du Y, Fan Z*. Natural Killer-like B Cells Prime Innate Lymphocytes against Microbial Infection. Immunity. 2016;45(1):131-44.

  15. Zhu P, Wang Y, Huang G, Ye B, Liu B, Wu J, Du Y, He L, Fan Z*. lnc-β-Catm elicits EZH2-dependent β-catenin stabilization and sustains liver CSC self-renewal. Nat Struct Mol Biol. 2016;23(7):631-9.

  16. Wang S, Xia P, Huang G, Zhu P, Liu J, Ye B, Du Y, Fan Z*. FoxO1-mediated autophagy is required for NK cell development and innate immunity. Nat Commun. 2016; 7:11023.

  17. Zhu P, Wang Y, Wu J, Huang G, Liu B, Ye B, Du Y, Gao G, Tian Y, He L, Fan Z*. LncBRM initiates YAP1 signalling activation to drive self-renewal of liver cancer stem cells. Nat Commun. 2016;7:13608.

  18. Li C, Du Y, Yang Z, He L, Wang Y, Hao L, Ding M, Yan R, Wang J*, Fan Z*. GALNT1-Mediated Glycosylation and Activation of Sonic Hedgehog Signaling Maintains the Self-Renewal and Tumor-Initiating Capacity of Bladder Cancer Stem Cells. Cancer Res. 2016;76(5):1273-83.

  2015

  19. Xia P, Wang S, Ye B, Du Y, Huang G, Zhu P, Fan Z*. Sox2 functions as a sequence-specific DNA sensor in neutrophils to initiate innate immunity against microbial infection. Nat Immunol. 2015; 16(4):366-375.

  20. Wang Y, He L, Du Y, Zhu P, Huang G, Luo J, Yan X, Ye B, Li C, Xia P, Zhang G, Tian Y, Chen R*, Fan Z*. The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling. Cell Stem Cell. 2015; 16(4):413-25.

  21. Zhu P, Wang Y, He L, Huang G, Du Y, Zhang G, Yan X, Xia P, Ye B, Wang S, Hao L, Wu J, Fan Z*. ZIC2-dependent OCT4 activation drives self-renewal of human liver cancer stem cells. J Clin Invest. 2015;125(10):3795-808.

  22. Xia P, Wang S, Du Y, Huang G, Satoh T, Akira S, Fan Z*. Insulin-InsR signaling drives multipotent progenitor differentiation toward lymphoid lineages. J Exp Med. 2015; 212(13):2305-21.

  23. Xia P, Wang S, Xiong Z, Ye B, Huang L, Han Z*, Fan Z*. IRTKS negatively regulates antiviral immunity through PCBP2 sumoylation-mediated MAVS degradation. Nat Commun. 2015;6:8132.

  24. Zhu P, Wang Y, Du Y, He L, Huang G, Zhang G, Yan X, Fan Z*. C8orf4 negatively regulates self-renewal of liver cancer stem cells via suppression of NOTCH2 signaling. Nat Commun. 2015; 6:7122.

  2014

  25. Xia P, Wang S, Huang G, Zhu P, Li M, Ye B, Du Y, Fan Z*. WASH is required for the differentiation commitment of hematopoietic stem cells in a c-Myc-dependent manner. J Exp Med. 2014;211(10): 2119-2134.

  26. Ye B, Li C, Yang Z, Wang Y, Hao J, Wang L, Li Y, Du Y, Hao L, Liu B, Wang S, Xia P, Huang G, Sun L, Tian Y*, Fan Z*. Cytosolic carboxypeptidase CCP6 is required for megakaryopoiesis by modulating Mad2 polyglutamylation. J Exp Med. 2014;211(12):2439-2454.

  27. Xia P, Wang S, Huang G, Du Y, Zhu P, Li M, Fan Z*. RNF2 is recruited by WASH to ubiquitinate AMBRA1 leading to downregulation of autophagy. Cell Res., 2014; 24:943–958.

  28. Li C, Yang Z, Du Y, Tang H, Chen J, Hu D, Fan Z. BCMab1, A Monoclonal Antibody against Aberrantly Glycosylated Integrin α3β1, Has Potent Antitumor Activity of Bladder Cancer In Vivo. Clin Cancer Res. 2014;20(15):4001-13.

  29. Ye B, Dai Z, Liu B, Wang R, Li C, Huang G, Wang S, Xia P, Yang X, Kuwahara K, Sakaguchi N, Fan Z. Pcid2 inactivates developmental genes in human and mouse embryonic stem cells to sustain their pluripotency by modulation of Eid1 stability. Stem Cells. 2014;32(3): 623-635.

  2013

  30. Wang S, Xia P, Ye B, Huang G, Liu J, Fan Z*. Transient activation of autophagy via Sox2-Mediated suppression of mTOR is an important early step in reprogramming to pluripotency. Cell Stem Cell. 2013;13(5):617–625.

  31. Xia P, Wang S, Du Y, Zhao Z, Shi L, Sun L, Huang G, Ye B, Li C, Dai Z, Hou N, Cheng X, Sun Q, Li L, Yang X, Fan Z*. WASH inhibits autophagy through suppression of Beclin 1 ubiquitination. EMBO J. 2013;32(20): 2685-2696.

  32. Liu S, Zhang H, Li M, Hu D, Li C, Ge B, Jin B, Fan Z*. Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells. Cell Death Differ. 2013;20(3):456-464.

  2012

  33. Wang S, Xia P, Shi L, Fan Z*. FADD cleavage by NK cell granzyme M enhances its self-association to facilitate procaspase-8 recruitment for auto-processing leading to caspase cascade. Cell Death Differ. 2012;19(4):605-615. (IF:8.8)

  34. Zhong C, Li C, Wang X, Toyoda T, Gao G, Fan Z*. Granzyme K inhibits replication of influenza virus through cleaving the nuclear transport complex importin α1/β dimer of infected host cells. Cell Death Differ. 2012;19(5):882-890.

  2011年以前文章

  35. Shi L, Wu L, Wang S, Fan Z*. Granzyme F induces a novel death pathway characterized by Bid-independent cytochrome c release without caspase activation. Cell Death Differ. 2009, 16(12): 1694-1706.

  36. Zhao T, Zhang H, Guo Y, Zhang Q, Hua G, Lu H, Hou Q, Liu H, Fan Z*. Granzyme K cleaves the nucleosome assembly protein SET to induce single-stranded DNA nicks of target cells. Cell Death Differ. 2007,14(3): 489-499.

  37. Fan Z*, Yu P, Wang Y, Wang Y, Fu ML, Liu W, Sun Y, Fu YX*. NK-cell activation by LIGHT triggers tumor-specific CD8+ T-cell immunity to reject established tumors. Blood. 2006, 107(4): 1342-1351.

  38. Fan Z*, Zhang H, Zhang Q. Tumor suppressor pp32 represses cell growth through inhibition of transcription by blocking acetylation and phosphorylation of histone H3 and initiating its proapoptotic activity. Cell Death Differ. 2006, 13(9): 1485-1494.

  39. Fan Z, Beresford PJ, Oh DY, Zhang D, Lieberman J*. Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Cell 2003, 112(5): 659-672.

  40. Fan Z, Beresford PJ, Zhang D, Xu Z, Novina CD, Yoshida A, Pommier Y, Lieberman J*. Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A. Nat Immunol. 2003, 4(2): 145-153.

  41. Lieberman J*, Fan Z*. Nuclear war: the granzyme A-bomb. Curr Opin Immunol. 2003, 15(5): 553-559.

  42. Fan Z, Beresford PJ, Zhang D, Lieberman J*. HMG2 interacts with the nucleosome assembly protein SET and is a target of the cytotoxic T-lymphocyte protease granzyme A. Mol Cell Biol. 2002, 22(8): 2810-2820.

  

  资料来源:范祖森研究员,2018-02-26网页更新

                 
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