报告人：范衡宇 浙江大学生命科学研究院教授、博士生导师
报告题目：生殖细胞发育与女性生殖健康的分子机理
时间：2013年6月3日（星期一）上午9:00
地点：北教学楼二楼大会议室
(记I类继教分2分)
范衡宇教授简介
一、教育和工作背景：
1993年9月-1997年7月：东北农业大学生物工程系 学士
1997年8月-2000年7月：东北农业大学生命科学学院 动物组织胚胎学硕士，导师：杨增明 教授
2000年8月-2003年7月：中国科学院动物研究所 生殖生物学博士，导师：孙青原 研究员
2003年8月-2006年7月：美国德克萨斯大学西南医学中心（UTSW）分子生物学系博士后
2006年7月-2009年12月：美国贝勒医学院（Baylor College of Medicine）分子与细胞生物学系博士后
2010年1月-至今：浙江大学生命科学研究院教授，博士生导师
二、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
三、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．利用小鼠和线虫为模型，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
四、研究业绩:
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PTEN和KrasG12D在诱导卵巢上皮细胞癌中的重要作用。
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 Reproduction和Molecular 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。
五、发表论文清单 (*通讯作者)：
1. 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. Mol Endocrinol. 2013 (in press)
2. Yu C, Zhang YL, Fan HY. Selective Smad4 knockout in ovarian preovulatory follicles results in multiple defects in ovulation. Mol Endocrinol. 2013 (in press)
3. Pan WW, Yi F, Cao L, Liu XM, Shen Z, Bu Y, Xu Y, Fan HY，Song F. DAXX silencing suppresses mouse ovarian surface epithelial cell growth by inducing senescence and DNA damage. Gene, 2013. (Accepted)
4. 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. (Accepted)
5. 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
6. 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
7. 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.
8. 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
9. 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
10.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
11.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
12.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
13.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
14.Fan HY, Richards JS. Physiological and pathological actions of RAS in the ovary. Molecular Endocrinology, 2010,24:286-298
15.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
16.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. (Comment in: Science, 2009, 324:938-941. New England Journal of Medicine, 2009, 361:718-719)
17.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.
18.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
19.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.
20.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.
21.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.)
22.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.
23.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.
24.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
25.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
26.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
27.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
28.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
29.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
30.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
31.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
32.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
33.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
34.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
35.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
36.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
37.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
38.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
39.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
40.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.
41.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.
42.Fan HY, Tong C, Chen DY, Sun QY. Roles of MAP kinase signaling pathway in meiosis of oocytes. Chinese Science Bulletin, 47:1157~1162
43.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
六、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
基础医学院 科研处
2013.05.29
