Uterine leukemia inhibitory factor (LIF), heparin-binding epidermal growth factor-like growth factor (HB-EGF), Hoxa-10 and cyclooxygenase-2 (COX-2) are essential to implantation success. The proposed hypothesis is that these genes participate in embryo-uterine interactions during implantation in a concerted manner via novel signaling pathways.
Specific aims are to determine in the mouse that: (1) an interaction of uterine EGF-like growth factors with the blastocyst EGF family of receptors is a prerequisite for the initiation of implantation; (2) prostaglandins (PGs) generated by the COX-2 pathway are involved in initiating implantation and subsequent decidualization; (3) PG synthesis is regulated in a spatiotemporal manner in the uterus; (4) PG effects on implantation and decidualization are mediated by nuclear receptors in the uterus; (5) further validation of the importance of the PG signaling pathway in these processes can be achieved using LIF and Hoxa-10 mutant mice. Several knockout mouse models with known defective implantation processes will be manipulated experimentally by molecular, cellular, biochemical and physiological techniques. The proposed research addresses two important global concerns on women's health issues: infertility and rapid population growth. Events of preimplantation embryo development and preparation for implantation are two of the major determinants of these concerns. Basic research to better understand these events will help alleviate problems of infertility, and aid in the development of new and improved contraceptive methods.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Method to Extend Research in Time (MERIT) Award (R37)
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Reproductive Biology Study Section (REB)
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Yoshinaga, Koji
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Vanderbilt University Medical Center
Schools of Medicine
United States
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Haraguchi, Hirofumi; Saito-Fujita, Tomoko; Hirota, Yasushi et al. (2014) MicroRNA-200a locally attenuates progesterone signaling in the cervix, preventing embryo implantation. Mol Endocrinol 28:1108-17
Cha, Jeeyeon; Bartos, Amanda; Egashira, Mahiro et al. (2013) Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions. J Clin Invest 123:4063-75
Sun, Xiaofei; Bartos, Amanda; Whitsett, Jeffrey A et al. (2013) Uterine deletion of Gp130 or Stat3 shows implantation failure with increased estrogenic responses. Mol Endocrinol 27:1492-501
Cha, Jeeyeon; Sun, Xiaofei; Bartos, Amanda et al. (2013) A new role for muscle segment homeobox genes in mammalian embryonic diapause. Open Biol 3:130035
Hirota, Yasushi; Burnum, Kristin E; Acar, Nuray et al. (2012) Galectin-1 markedly reduces the incidence of resorptions in mice missing immunophilin FKBP52. Endocrinology 153:2486-93
Sun, Xiaofei; Zhang, Liqian; Xie, Huirong et al. (2012) Kruppel-like factor 5 (KLF5) is critical for conferring uterine receptivity to implantation. Proc Natl Acad Sci U S A 109:1145-50
Burnum, Kristin E; Hirota, Yasushi; Baker, Erin S et al. (2012) Uterine deletion of Trp53 compromises antioxidant responses in the mouse decidua. Endocrinology 153:4568-79
Cha, Jeeyeon; Hirota, Yasushi; Dey, Sudhansu K (2012) Sensing senescence in preterm birth. Cell Cycle 11:205-6
Cha, Jeeyeon; Sun, Xiaofei; Dey, Sudhansu K (2012) Mechanisms of implantation: strategies for successful pregnancy. Nat Med 18:1754-67
Hirota, Yasushi; Cha, Jeeyeon; Yoshie, Mikihiro et al. (2011) Heightened uterine mammalian target of rapamycin complex 1 (mTORC1) signaling provokes preterm birth in mice. Proc Natl Acad Sci U S A 108:18073-8

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