范衡宇 博士
浙江大学生命科学研究院教授、研究员、博士生导师
办公地点：医学院科研楼A305
电话：0571-88981582 (office)
传真：0571-88981582
Email:hyfan@zju.edu.cn
实验室网站：http://lsi.zju.edu.cn/yjdw_detail.aspx?ID=8
教育和工作背景
1993-1997：东北农业大学生物工程系 学士
1997-2000：东北农业大学生命科学学院 动物组织胚胎学硕士
2000-2003：中国科学院动物研究所 生殖生物学博士
2003-2006：美国德克萨斯大学西南医学中心（UTSW）分子生物学系博士后
2006-2009：美国贝勒医学院（Baylor College of Medicine）分子与细胞生物学系博士后
2010-至今： 浙江大学生命科学研究院教授，研究员，博士生导师
详细介绍：
学术奖项与活动
2003： 中国科学院 院长优秀奖
2009： Ruth L. Kirschstein National Research Service Award, National Institute of Health, USA.
2009： Lalor Foundation Merit Award
2007-至今： Membership of the Society for the Study of Reproduction.
研究方向
本实验室主要研究哺乳动物卵巢功能的分子调节机理以及卵巢相关疾病的发生机理。
卵巢作为雌性生殖器官，其功能主要是产生成熟的雌性生殖细胞（卵母细胞）并分泌性激素。哺乳动物卵巢主要由处于不同发育阶段的卵泡和黄体组成。卵泡的发育、排卵和黄体化受到两种促性腺激素FSH和LH的紧密调控。我们利用多种卵泡颗粒细胞或卵母细胞特异性的基因敲除小鼠和转基因小鼠，研究促性腺激素激活的信号通路及其靶基因对卵巢功能的调节作用。我们最近的研究揭示，PI3K/AKT信号通路参与调节颗粒细胞增殖或凋亡，而RAS/ERK1/2信号途径是LH诱导卵母细胞成熟、排卵和黄体化过程所必需的。通过基因芯片分析，我们鉴定出了小鼠基因组中所有在排卵过程中受到LH调节的基因，并进一步确定了哪些LH靶基因的表达依赖于RAS/ERK1/2信号通路的激活。在进一步的研究中，我们将继续分析这些新发现的LH靶基因在卵巢中的功能，以及其他重要信号通路对卵泡发育和排卵的调节作用。
当这些调节卵巢正常功能的信号分子发生遗传缺失或过度激活，就会导致各种卵巢疾病，比如卵巢早衰、多囊卵巢综合症和卵巢肿瘤。本实验室也将综合利用转基因小鼠模型和人类临床样本，研究重要基因和信号通路在这些卵巢疾病发生中的作用。
上述工作，不仅可以推动哺乳动物生殖与发育生物学的基础研究，也在医学临床实践（如辅助生殖、计划生育、内分泌疾病和卵巢癌的治疗）、经济动物养殖和珍稀野生动物保护等领域具有重要的理论指导作用。
Research interests:
My major research interest is to dissect the signaling pathways and their target genes that regulate the ovarian functions in mammalian species.
Ovary is the female reproductive organ that produces fertilizable female germ cells (oocytes) and sexual hormones. Follicle development, ovulation and luteinization are tightly regulated by follicle-stimulating hormone (FSH) and luteinizing hormone (LH). I have generated multiple granulosa cell or oocyte-specific gene knockout and transgenic mouse models, to dissect the gonadotropin-activated signaling pathways and their target genes that regulate the ovarian functions. My recent studies have shown that the PI3K/AKT pathway is involved in the regulation of granulosa cell proliferation and apoptosis, whereas EGF receptor/RAS/ERK1/2 cascade is essential for LH-induced oocyte maturation, ovulation and luteinization. By microarray analysis, I have identified numerous LH regulated genes during ovulation, and determined which of them are under the control of RAS/ERK1/2 cascade. We will continue to investigate the functions of these novel LH target genes in the mammalian ovaries, as well as other signaling molecules involved in follicle development and ovulation.
While the precisely regulated signaling events maintain the normal ovarian functions, the aberrant expressions or activations of essential signaling molecules lead to ovarian disorders such as premature ovarian failure (POF), polycystic ovarian syndrome (PCOS) and ovarian cancers. I will also study several conditional mutant mouse strains that develop ovarian cancers (both granulosa cell tumors and ovarian surface epithelial tumors) in addition to reproductive defects.
These studies will not only contribute to the basic research of mammalian reproductive biology, but also have potentials of wide application in human clinics (i.e. contraception, assistant reproduction, therapies of endocrine disease and ovarian cancers), farm animal reproduction, and genetic conservation of endangered mammalian species.
代表性论文
1. 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(me.2010‐0141)
2. Liu Z, Fan HY, Wang Y, Richards JS. Targeted disruption of MAPK14 (p38MAPK alpha) ingranulosa cells and cumulus cells causes cell specific and compensatory changes in geneexpression profiles that maintain fertility in vivo. Molecular Endocrinology, 2010(me.2010‐0138)
3. Fan HY, Richards JS. Physiological and pathological actions of RAS in the ovary. Molecular Endocrinology, 2010 ,24:286‐298 【PDF download 】
4. 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 【PDF download 】
5. 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) 【PDF download】
6. 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.
7. Liu Z, de Matos DG, Fan HY, Shimada M, Palmer S, Richards JS. (2009). Interleukin-6: an autocrine regulator of the mouse cumulus cell-oocyte complex expansion process. Endocrinology 150(7): 3360-8. 【PDF download】
8. Liu Z, Rudd MD, Hernandez-Gonzalez I, Gonzalez-Robayna I, Fan HY, Zeleznik AJ, Richards JS. FSH and FOXO1 regulate genes in the sterol/steroid and lipid biosynthetic pathways in granulosa cells . Molecular Endocrinology, 2009 23:649-661. 【PDF download】
9. 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. 【PDF download 】
10. 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.) 【PDF download 】
11. 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.
12. 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. 【PDF download 】
13. 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
14. 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 【PDF download 】
15. 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 【PDF download 】
16. 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 【PDF download 】
17. 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 its functional roles in the regulation of meiotic maturation ,fertilization and cleavage. Molecular Reproduction and Development, 2003 65:318-329
18. 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 【PDF download 】
19. 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 【PDF download 】
20. 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 【PDF download 】
21. 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
22. 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