The overall goal of this proposal is to understand the function of the EGF network during the LH-induced ovulatory process. Preliminary studies from our laboratory indicate that three members of the EGF-like growth factor family (epiregulin/EREG, amphiregulin/AREG, and betacellulin/BTC) are induced by LH at the time of ovulation and that exogenous application of these factors to cultured follicles recapitulates several effects of LH, including oocyte resumption of meiosis and cumulus expansion. In addition, an indispensable role of EGF receptor signaling in LH action during ovulation is suggested by pharmacological and preliminary genetic studies. On the basis of these findings, we propose the hypothesis that LH regulation of the EGF network is critical for the ovulatory process. Studies to test this hypothesis are organized into three specific aims. With the first specific aim, we will investigate the impact of ablation of several genes of the EGF network on the ovulatory process in vivo. Mice with deletion of the AREG or EREG gene and with compound mutations affecting a ligand and the EGF receptor will be studied for reproductive phenotypes. With the second specific aim, the synthesis and processing of EGF-like growth factors, as well as the regulation of their secretion, will be investigated in in vitro models of granulosa cells and intact follicles. The third specific aim will be devoted to understanding how EGF receptor signaling is integrated in the signaling cascades activated by gonadotropins during the periovulatory period. These studies will contribute to our understanding of the physiology of ovulation, a process critical for fertility. They will also provide the rational basis to design pharmacological strategies to manipulate fertility or to improve culture conditions for in vitro nuclear and cytoplasmic maturation of oocytes. Finally, a better understanding of the function of EGF-like growth factors will contribute to the understanding of the biology of some tumors of gynecological interest.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD052909-06
Application #
8049723
Study Section
Special Emphasis Panel (ZRG1-EMNR-E (03))
Program Officer
Taymans, Susan
Project Start
2007-04-01
Project End
2013-03-31
Budget Start
2011-04-01
Budget End
2013-03-31
Support Year
6
Fiscal Year
2011
Total Cost
$316,580
Indirect Cost
Name
University of California San Francisco
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Peluffo, Marina C; Hennebold, Jon D; Stouffer, Richard L et al. (2013) Oocyte maturation and in vitro hormone production in small antral follicles (SAFs) isolated from rhesus monkeys. J Assist Reprod Genet 30:353-9
Peluffo, Marina C; Ting, Alison Y; Zamah, Alberuni M et al. (2012) Amphiregulin promotes the maturation of oocytes isolated from the small antral follicles of the rhesus macaque. Hum Reprod 27:2430-7
Conti, Marco; Hsieh, Minnie; Zamah, A Musa et al. (2012) Novel signaling mechanisms in the ovary during oocyte maturation and ovulation. Mol Cell Endocrinol 356:65-73
Chen, Jing; Melton, Collin; Suh, Nayoung et al. (2011) Genome-wide analysis of translation reveals a critical role for deleted in azoospermia-like (Dazl) at the oocyte-to-zygote transition. Genes Dev 25:755-66
Oh, Jeong Su; Susor, Andrej; Conti, Marco (2011) Protein tyrosine kinase Wee1B is essential for metaphase II exit in mouse oocytes. Science 332:462-5
Hsieh, Minnie; Thao, Kao; Conti, Marco (2011) Genetic dissection of epidermal growth factor receptor signaling during luteinizing hormone-induced oocyte maturation. PLoS One 6:e21574
Jin, S-L Catherine; Goya, Sho; Nakae, Susumu et al. (2010) Phosphodiesterase 4B is essential for T(H)2-cell function and development of airway hyperresponsiveness in allergic asthma. J Allergy Clin Immunol 126:1252-9.e12
Zamah, A M; Hsieh, M; Chen, J et al. (2010) Human oocyte maturation is dependent on LH-stimulated accumulation of the epidermal growth factor-like growth factor, amphiregulin. Hum Reprod 25:2569-78
Conti, M (2010) Signaling networks in somatic cells and oocytes activated during ovulation. Ann Endocrinol (Paris) 71:189-90

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