范衡宇教授

文章出处: 作者: 发布时间: 2015-02-13 访问次数: 719

 

范衡宇教授

浙江大学,生命科学研究院,教授

19756月生于黑龙江省哈尔滨市

 

受教育经历:

2000/09–2003/07,中国科学院动物研究所,计划生育生殖生物学国家重点实验室,博士,导师:孙青原研究员

1997/09–2000/06,东北农业大学,生命科学学院,硕士,导师:杨增明教授

1993/09–1997/06,东北农业大学,生物工程系,学士

 

研究工作经历

2010/01–至今,浙江大学,生命科学研究院,教授

2006/07–2010/01,美国贝勒医学院(Baylor College of Medicine),细胞与分子生物学系,博士后

2003/07–2006/06,美国德克萨斯大学西南医学中心(University of Texas Southwestern Medical Center),分子生物学系,博士后

 

学术奖项与活动:

2002:中国科学院动物研究所优秀研究生奖

2003:中国科学院院长优秀奖

2009:美国国立卫生研究院杰出研究奖学金 (Ruth L. Kirschstein National Research Service Award, National Institute of Health, USA).

2009:北美生殖生物学会优秀研究奖 (Lalor Foundation Merit Award)

2010:国际卵巢生物学会杰出青年科学家奖

2010:浙江省杰出青年基金获得者

2013-至今:Endocrinology编委会成员

2013-至今:中国动物学会生殖生物学分会常务理事

2014-至今:中国动物学会细胞与分子显微技术学分会副理事长

 

实验室研究方向:

1:利用基因敲除和条件基因敲除技术研究激素在生殖发育过程中的信号传导

2:利用小鼠为模型,研究生殖干细胞的维持、分化,减数分裂和重编程的分子机制

3:建立癌症动物模型,研究生殖系统肿瘤的发生机制和潜在的治疗手段

 

个人简介:

长期从事哺乳动物生殖生物学研究,并在该领域取得一系列重要成果:

1)早期研究集中在蛋白激酶在哺乳动物卵母细胞减数分裂和受精中的作用。利用小鼠、大鼠和猪卵母细胞为实验模型,提出蛋白激酶C亚型调节卵皮质颗粒释放,Polo-like激酶和钙调蛋白依赖的蛋白激酶参与调节卵母细胞减数分裂,促性腺激素通过激活MAPK诱导卵母细胞减数分裂成熟。相关文章在Biology of Reproduction, Cell Cycle, Experimental Cell Research等国际主流期刊上发表,并获得中国科学院院长优秀奖和中国科学院动物研究所优秀研究生等荣誉。

2)最早克隆了模式生物非洲爪蟾的Separase基因,并研究了该基因在减数分裂染色体分离过程中的作用,以及细胞周期过程中Separase蛋白酶活性的调节机制。

3)近年来,建立了卵巢颗粒细胞特异性的基因敲除小鼠模型,并成功应用该技术研究了多个重要信号转导分子和癌基因在卵巢中的功能。发现促性腺激素通过激活小G蛋白RAS和蛋白激酶ERK1/2,诱导卵母细胞成熟、排卵和黄体形成。用基因芯片技术筛选出小鼠基因组中所有受促性腺激素和ERK1/2调节的排卵相关基因,并用条件基因敲除技术证明C/EBP beta是卵巢颗粒细胞中重要的ERK1/2下游靶基因。通过这些研究,建立了促性腺激素诱导排卵的关键信号转导网络和基因表达谱。

4)在卵巢癌相关基因的研究中,发现抑癌基因PETN在调节卵泡生长、卵泡闭锁、排卵数目和黄体细胞寿命等方面具有重要作用。发现癌基因KrasG12D 诱导卵泡发育异常,导致雌性动物生殖力下降,发生卵巢早衰。建立了卵巢颗粒细胞癌和浆液性卵巢上皮细胞癌的小鼠模型,发现了PTENKrasG12D在诱导卵巢上皮细胞癌中的重要作用。

5)以小鼠模型研究CRL4复合体在雌性生殖力维持尤其是卵母细胞存活中的作用,多层次、多角度地分析CRL4功能缺失造成不孕不育的原因,阐明其在调节卵母细胞表观遗传以及在不同生殖过程中的作用,为人类中女性卵巢早衰和不孕不育的病因提供新的理解。本研究从全新的视角探讨生殖障碍的分子基础,具有重要的医学应用价值,从而为临床上的雌性生殖力保护及卵母细胞体外成熟培养等提供具有现实意义的指导性方案。

上述研究为揭示特定基因在卵巢中的生理功能和病理影响开辟了道路。相关研究发表在Science, Development, Cancer Research, Molecular Endocrinology等国际生物学和生殖内分泌学权威期刊上。研究成果受到Science, New England Journal of Medicine, Nature Medicine等其他生物、医学著名期刊的关注,并发表相关评论文章。受邀为生殖、内分泌领域权威期刊Biology of ReproductionMolecular Endocrinology 撰写综述文章。2008年获得美国国立卫生研究院Ruth L. Kirschstein国家研究奖,2009年在美国生殖生物学年会上获得Lalor基金会优秀研究奖,2010年在第17届国际卵巢生物学大会上获得最佳青年科学家奖。

 

发表论文清单 (*通讯作者)

1.    Yu C, Zhang YL, Pan WW, Li XM, Wang ZW, Ge ZJ, Zhou JJ, Cang Y, Tong C, Sun QY*, Fan HY*. CRL4 complex regulates mammalian oocyte survival and reprogramming by activation of TET proteins. Science 2013, 342:1518-1521

2.    Fan HY, Liu Z, Shimada M, Sterneck E, Johnson PF, Hedrick SM, Richards JS. MAPK3/1 (ERK1/2) in ovarian granulosa cells are essential for female fertility. Science, 2009, 324:938-941.

3.    Yu C, Xu YW, Sha QQ, Fan HY*. CRL4DCAF1 is required in activated oocytes for follicle maintenance and ovulation. Molecular Human Reproduction, 2014, accepted.

4.    Xia Y, Zhang YL, Yu C, Chang Ting, Fan HY*. YAP/TEAD co-activator regulated pluripotency and chemoresistance in ovarian cancer initiated cells. PLoS One. 2014, accepted.

5.    Zhang YL, Yu C, Richards JS, Liu J, Fan HY*. CBP-CITED4 is required for luteinizing hormone-triggered target gene expression during ovulation. Molecular Human Reproduction, 2014, 20, 850-860

6.    Pan H, Cui H, Liu S, Qian Y, Wu H, Li L, Guan Y, Guan X, Zhang L, Fan HY, Ma Y, Li R, Liu M, Li D. Lgr4 Gene Regulates Corpus Luteum Maturation Through Modulation of the WNT-Mediated EGFR-ERK Signaling Pathway. Endocrinology. 2014 Sep;155(9):3624-37.

7.    Jiang ZZ, Hu MW, Wang ZB, Huang L, Lin F, Qi ST, Ouyang YC, Fan HY, Schatten H, Mak TW, Sun QY. Survivin is essential for fertile egg production and female fertility in mice. Cell Death Dis. 2014 Mar 27;5:e1154. doi: 10.1038/cddis.2014.126.

8.    Xia Y, Chang T, Wang Y, Liu Y, Li W, Li M, Fan HY*. YAP promotes ovarian cancer cell tumorigenesis and is indicative of a poor prognosis for ovarian cancer patients. PLoS One. 2014 Mar 12;9(3):e91770. doi: 10.1371/journal.pone.0091770. eCollection 2014.

9.    Zhang YL, Yu C, Ji SY, Li XM, Zhang YP, Zhang D, Zhou D, and Fan HY*. TOP2β is essential for ovarian follicles that are hypersensitive to chemotherapeutic drugs. Molecular Endocrinology, 2013 27(10):1678-1691

10.  Wang ZW, Ma XS, Ma JY, Luo YB, Lin F, Wang ZB, Schatten H, Fan HY, Sun QY. Laser microbeam-induced DNA damage inhibits cell division in fertilized eggs and early embryos. Cell Cycle, 2013, 12(20).

11.  Pan WW, Zhou JJ, Xu Y, Guo LJ, Yu C, Zhou D, Song FZ, Fan HY*. CRL4CDT2/DCAF2 ubiquitin E3 ligase as a potential chemotherapeutic target for ovarian surface epithelial cancer. J Biol Chem, 2013, 288(41):29680-29691

12.  Li XM, Yu C, Wang ZW, Zhang YL, Liu XM, Sun QY and Fan HY*. DNA topoisomerase II is dispensable for oocyte meiotic resumption but is essential for meiotic chromosome condensation and separation. Biology of Reproduction, 2013 89(5): 1–11

13.  Li Q, He H, Zhang YL, Li XM, Guo X, Huo R, Bi Y, Li J, Fan HY*, Sha J*. Phosphoinositide 3-kinase p110δ Mediates Estrogen- and FSH-Stimulated Ovarian Follicle Growth. Molecular Endocrinology. 2013, 27(9):1468-1482

14.  Yu C, Zhang YL, Fan HY*. Selective Smad4 knockout in ovarian preovulatory follicles results in multiple defects in ovulation. Molecular Endocrinology. 2013 27(6):966-978

15.  Pan WW, Yi F, Cao L, Liu XM, Shen Z, Bu Y, Xu Y, Fan HYSong F. DAXX silencing suppresses mouse ovarian surface epithelial cell growth by inducing senescence and DNA damage. Gene, 2013, 526(2):287-294

16.  Pan WW, Zhou JJ, Liu XM, Xu Y, Guo LJ, Yu C, Shi QH, Fan HY*. Death domain-associated protein DAXX promotes ovarian cancer development and chemoresistance. J Biol Chem, 2013. 288(19):13620-13630

17.  Qiu Z, Liu M, Chen Z, Shao Y, Pan H, Wei G, Yu C, Zhang L, Li X, Wang P, Fan HY, Du B, Liu B, Liu M, Li D. High-efficiency and heritable gene targeting in mouse by transcription activator-like effector nucleases. Nucleic Acids Res. 2013 41(11): e120

18.  Huang L, Wang ZB, Jiang ZZ, Hu MW, Lin F, Zhang QH, Luo YB, Hou Y, Zhao Y, Fan HY, Schatten H, Sun QY. Specific disruption of Tsc1 in ovarian granulosa cells promotes ovulation and causes progressive accumulation of corpora lutea. PLoS One. 2013;8(1):e54052

19.  Fan HY, Liu Z, Mullany LK, Richards JS. Consequences of RAS and MAPK activation in the ovary: The good, the bad and the ugly. Mol Cell Endocrinol. 2012 5;356(1-2):74-9.

20.  Richards JS, Fan HY, Liu Z, Tsoi M, Laguë MN, Boyer A, Boerboom D. Either Kras activation or Pten loss similarly enhance the dominant-stable CTNNB1-induced genetic program to promote granulosa cell tumor development in the ovary and testis. Oncogene 2012 Mar 22;31(12):1504-20

21.  Mullany LK, Fan HY, Liu Z, White LD, Marshall A, Gunaratne P, Anderson ML, Creighton CJ, Xin L, Deavers M, Wong KK, Richards JS. Molecular and functional characteristics of ovarian surface epithelial cells transformed by KrasG12D and loss of Pten in a mouse model in vivo. Oncogene 2011, 30, 3522–3536

22.  Fan HY, Liu Z, Johnson PF, Richards JS. CCAAT/Enhancer binding proteins (C/EBP)-α and -β are essential for ovulation, luteinization and the expression of key target genes. Molecular Endocrinology, 2011, 25(2): 253-268

23.  Noma N, Kawashima I, Fan HY, Fujita Y, Kawai T, Tomoda Y, Mihara T, Richards JS, and Shimada M. LH-induced neuregulin 1 (NRG1) type III transcripts control granulosa cell differentiation and oocyte maturation. Molecular Endocrinology, 2011 (1):104-16

24.  Fan HY, O’connor A, Shitanaka M, Shimada M, Liu Z, Richards JS. Beta-catenin (CTNNB1) promotes preovulatory follicular development but represses luteinizing hormone-mediated ovulation and luteinization. Molecular Endocrinology, 2010, 24(8):1529-1542

25.  Fan HY. BubR1, a spindle assembly checkpoint protein in mammalian oocyte meiosis. Cell Cycle. 2010, 9(8):1458

26.  Liu Z, Fan HY, Wang Y, Richards JS. Targeted disruption of MAPK14 (p38MAPK alpha) in granulosa cells and cumulus cells causes cell specific and compensatory changes in gene expression profiles that maintain fertility in vivo. Molecular Endocrinology, 2010 24(9):1794-804

27.  Fan HY, Richards JS. Physiological and pathological actions of RAS in the ovary. Molecular Endocrinology, 2010,24:286-298

28.  Fan HY, Liu Z, Paquet M, Wang J, Lydon JP, DeMayo FJ, Richards JS.  Cell type-specific targeted mutations of Kras and Pten document proliferation arrest in granulosa cells versus oncogenic insult to ovarian surface epithelial cells. Cancer Research, 2009, 69:6463-6472

29.  Sun Y, Kucej M, Fan HY, Yu H, Sun QY, Zou H. Separase is recruited to mitotic chromosomes to dissolve sister chromatid cohesion in a DNA-dependent manner. Cell, 2009, 137:123-132.

30.  Liu Z, de Matos DG, Fan HY, Shimada M, Palmer S, Richards JS. IL6: a potent regulator of the mouse cumulus cells-oocyte complex expansion process. Endocrinology, 2009, 150:3360-3368

31.  Liu Z, Rudd MD, Hernandez-Gonzalez I, Gonzalez-Robayna I, Fan HY, Zeleznik AJ, Richards JS. Genes in sterol/steroid and lipid biosynthetic pathways are targets of FSH and FOXO1 regulation in granulosa cells: evidence from cells expressing mutant forms of FOXO1. Molecular Endocrinology, 2009 23:649-661.

32.  Laguë MN, Paquet M, Fan HY, Kaartinen MJ, Chu S, Jamin SP, Behringer RR, Fuller PJ, Mitchell A, Doré M, Huneault LM, Richards JS, Boerboom D. Synergistic effects of Pten loss and WNT/CTNNB1 signaling pathway activation in ovarian granulosa cell tumor development and progression. Carcinogenesis, 2008, 29(11):2062-2072.

33.  Fan HY, Liu Z, Cahill N, Richards JS. Targeted disruption of Pten in ovarian granulosa cells enhances ovulation and extends the life span of luteal cells. Molecular Endocrinology, 2008, 22(9):2128-2140. (Comment in Nature Medicine, 2008, 11:1192-1193.)

34.  Fan HY, Shimada M, Liu Z, Cahill N, Noma N, Wu Y, Gossen J, Richards JS. Selective expression of KrasG12D in granulosa cells of the mouse ovary causes defects in follicle development and ovulation. Development, 2008, 135:2127-2137.

35.  Wayne CW, Fan HY, Cheng X, and Richards JS. FSH-induces multiple signaling cascades: evidence that activation of SRC, RAS and the EGF receptor are critical for granulosa cell differentiation. Molecular Endocrinology, 2007, 21:1940-1957.

36.  Fan HY, Sun QY, Zou H. Regulation of separase in meiosis: separase is activated at the metaphase I-II transition in Xenopus oocytes during meiosis. Cell Cycle, 2006, 10:198-204

37.  Fan HY, Huo LJ, Schatten H, Chen DY, Sun QY. Protein kinase C and MAPK cascade in mouse cumulus cells: crosstalk and effect on meiotic resumption of oocyte. Biology of Reproduction, 2004, 70:1178-1187

38.  Fan HY, Sun QY. Involvement of mitogen-activated protein kinase Cascade during oocyte maturation and fertilization in mammals. Biology of Reproduction, 2004, 70(3):535-547

39.  Fan HY, Tong C, Teng CB, Lian L, Li SW, Yang ZM, Chen DY, Schatten H, Sun QY. Characterization of Polo-like kinase-1 in rat oocytes and early embryos implies it’s functional roles in the regulation of meiotic maturation and cleavage. Molecular Reproduction and Development, 2003 65:318-329

40.  Fan HY, Huo LJ, Meng XQ, Zhong ZS, Hou Y, Chen DY, Sun QY. Involvement of calcium/calmodulin-dependent protein kinase II (CaMKII) in the meiotic maturation and activation of pig oocytes. Biology of Reproduction, 2003, 69:1552-1564

41.  Fan HY, Tong C, Lian L, Li SW, Gao WX, Cheng Y, Chen DY, Schatten H, Sun QY. Characterization of ribosomal S6 protein kinase p90rsk during meiotic maturation and fertilization in pig oocytes: MAPK-associated activation and localization. Biology of Reproduction, 2003, 68:968-977

42.  Tong C, Fan HY, Lian L, Li SW, Chen DY, Schatten H, Sun QY. Polo-like kinase 1 is a pivotal regulator of micrutubule assembly during mouse oocyte meiotic maturation, fertilization, and early embryonic mitosis. Biology of Reproduction, 2002, 67:546-554

43.  Fan HY, Li MY, Tong C, Chen DY, Xia GL, Song XF, Schatten H, Sun QY. Inhibitory effects of cAMP and protein kinase C on meiotic maturation and MAP kinase phosphorylation in porcine oocytes. Molecular Reproduction and Development, 2002, 63: 480-487

44.  Fan HY, Tong C, Li MY, Lian L, Chen DY, Schatten H, Sun QY. Translocation of classical protein kinase C (cPKC) isoforms in porcine oocytes: implications of PKC involvement in the regulation of nuclear activity and cortical granule exocytosis. Experimental Cell Research, 2002, 277:183-191

45.  Liang CG, Su YQ, Fan HY, Schatten H and Sun QY. Mechanisms regulating oocyte meiotic resumption: roles of mitogen-activated protein kinase. Molecular Endocrinology, 2007, 21, 2037-2055

46.  Tong C, Fan HY, Li SW, Chen DY, Schatten H, Song XF, Sun QY. Effects of MEK inhibitor U0126 on meiotic progression in mouse oocyte: microtuble organization, asymmetric division and metaphase II arrest. Cell Research, 2003, 13:375~383

47.  Huo LJ, Fan HY, Zhong ZS, Schatten H, Chen DY, Sun QY. Involvement of ubiquitin-proteasome pathway in mouse oocyte meiotic maturation, fertilization and early embryonic cleavage. Mechanisms of Development, 2004 121(10):1275-1287

48.  Huo LJ, Fan HY, Liang CG, Yu LZ, Zhong ZS, Schatten H, Chen DY, Sun QY. Regulation of ubiquitin-proteasome pathway on pig oocyte meiotic maturation and fertilization. Biology of Reproduction, 2004, 71(3):853-862

49.  Cheng Y, Fan HY, Wen DC, Tong C, Zhu ZY, Lei L, Sun QY, Chen DY. Asynchronous cytoplast and karyoplast transplantation reveals that the cytoplasm determines the developmental fate of the nucleus in mouse oocytes. Molecular Reproduction and Development, 2003 65:278~282

50.  Yao LJ, Fan HY, Tong C, Chen DY, Sun QY. Polo-like kinase-1 in porcine oocyte meiotic maturation, fertilization and early embryonic mitosis. Cellular and Molecular Biology, 2003, 49(3):399-405

51.  Quan HM, Fan HY, Meng XQ, Huo LJ, Chen DY, Schatten H, Yang PM, Sun QY. Effects of PKC activation on the meiotic maturation, fertilization, and early embryonic development of mouse oocytes. Zygote, 2003, 11 (4):329-337

52.  Meng XQ, Fan HY, Zhong ZS, Zhang G, Li YL, Chen DY, Sun QY. Localization of gamma-tubulin in mouse eggs during meiotic maturation, fertilization, and early embryonic development. Journal of Reproduction and Development, 2004, 50 (1):97-105.

53.  Huo LJ, Yu LZ, Liang CG, Fan HY, Chen DY, Sun QY. Cell cycle-dependent subcellular localization of cyclin B1, phosphorylated cyclin B1 and p34cdc2 during oocyte meiotic maturation and fertilization in mouse. Zygote. 2005, 13(1):45-53.

54.  Fan HY, Tong C, Chen DY, Sun QY. Roles of MAP kinase signaling pathway in meiosis of oocytes. Chinese Science Bulletin, 47:1157~1162 

55.  Fan HY, Tong C, Chen DY, Sun QY. Roles of protein kinase C in meiotic maturation and fertilization of oocytes. Progress in Natural Science, 2003, 13:401-406

56.范衡宇,佟超,陈大元,孙青原:蛋白激酶在卵母细胞减数分裂成熟和受精中的作用。生物化学与生物物理学报,200234: 259-265

57.范衡宇,佟超,李满玉,孙青原:用激光共聚焦显微术在小鼠卵母细胞中检测蛋白激酶C。生物化学与生物物理进展,2001, 28: 900-903

58.范衡宇,佟超,孙青原:核糖体S6蛋白激酶p90rsk与卵母细胞减数分裂。生物化学与生物物理进展,200229: 506-509

59.范衡宇,孟小倩,霍立军,佟超,陈大元,孙青原. Detection of spindle-associated proteins in mammalian oocytes by confocal microscopy.生物化学与生物物理进展, 2004, 311: 54-58

60.范衡宇,佟超,李世文,陈大元,孙青原:Microtubule organization during in vitro development of rat oocytes.生物化学与生物物理进展,2002, 29 (5): 708-713

61.范衡宇,霍立军,孙青原:Roles of calmodulin-dependent protein kinase II in meiotic maturation and fertilization of oocytes.生物化学与生物物理进展,2003, 30 (2) 171-174

62.范衡宇,白玉妍,杨增明:胚泡着床窗口的分子调控。生物化学与生物物理进展,2001, 28:11-16

63.Li MY, Fan HY, Tong C, Chen DY, Xia GL, Sun QY. Mitogen-activated protein kinase regulates cell cycle progression in pig oocytes and fertilized eggs. Chinese Science bulletin, 2002, 47: 843-847

64.霍立军,范衡宇,陈大元,孙青原. 卵母细胞减数分裂和受精过程中MAPKMPF的作用和相互调节. 自然科学进展, 2004,14: 256-261

65.白玉妍,范衡宇,杨增明:同源盒基因与哺乳动物生殖。生物化学与生物物理进展,2001, 28: 329-332

66.范衡宇,佟超,李世文,陈大元,孙青原:蛋白激酶C在小鼠卵母细胞成熟和受精中的作用。实验生物学报,2003, 36(1): 37-42

67.范衡宇,杨增明:乙醇对小鼠着床前胚胎体外发育的影响。动物学报,2001, 47(1): 85-88

68.范衡宇,杨增明:催产素及其受体与哺乳动物的生殖。动物学报,2001, 47(4):453-458

69.范衡宇,佟超,孙青原:丝裂原活化蛋白激酶(MAPK)信号通路的研究进展。动物学杂志, 2002, 37: 98-102

70.范衡宇,佟超,孙青原:丝裂原活化蛋白激酶(MAPK)信号通路与受精。生命的化学,200121(4): 308~310

71.范衡宇:与“implantation”相关的几个概念的讨论。细胞生物学杂志,2001, 23: 230-231

72.佟超,范衡宇,陈大元,孙青原:Parthenogenetic activation of mouse eggs induced by cycloheximide is calcium-dependent and can be blocked by okadaic acid.动物学报, 2002, 48: 749-753

73.佟超,范衡宇,李满玉,陈大元,孙青原:Polo like激酶在细胞分裂中的作用研究进展。生理科学进展,200233: 45-47

74.霍立军,范衡宇,陈大元,孙青原:泛素-蛋白水解酶信号通路在卵母细胞减数分裂和受精中的作用。细胞生物学杂志, 2003, 25(2):73-77

75.范衡宇,杨增明:前列腺素及其受体与哺乳动物的生殖。生理科学进展,2000, 31(1): 75-78

 

参编专著

1     Heng-Yu Fan, Qing-Yuan Sun: In vitro maturation and fertilization of pig oocytes. In H. Schatten eds: Methods in Molecular Medicine: Germ Cells. Humana Press, USA, 2004; 253:227-234.

2     Qing-Yuan Sun, Heng-Yu Fan: Activity of MAPK/p90rsk pathway during fertilization. In H. Schatten eds: Methods in Molecular Medicine: Germ Cells. Humana Press, USA, 2004; 253:293-304

3   范衡宇孙青原: 生殖生物学:第18章现代生殖生物学研究方法和技术简介。科学出版社(2004

4   范衡宇(译著)小鼠胚胎操作:第2章小鼠发育概要。化学工业出版社(进行中)