The sex steroid hormones, estrogen and progesterone, via their cognate receptors, play critical roles in uterine receptivity, implantation, and decidualization, enabling the effective establishment and maintenance of early pregnancy. The action of estrogens through the estrogen receptor (ER) are critically dependent on coregulator partner proteins, and we have shown that the ER-selective corepressor REA (for Represser of Estrogen receptor Activity) serves as a brake on estrogen activities in the uterus and is important in embryo development, uterine function and fertility. Further, aromatase expression and locally produced estrogen in the early pregnancy uterus is not only required for implantation, but also critically regulates the decidualization program. In addition, our recent findings reveal REA abundance is strikingly reduced in endometriosis vs. normal human endometrium. Thus, our goals in this project are to elucidate the role of REA using a conditional REA knockout mouse we are generating, with which we can study the effects of conditional deletion of this corepressor on fertility and the uterine reproductive phenotype during early stages of pregnancy. Analysis of how REA and REA-associated partner proteins, as well as other corepressors, affect ER-regulated gene networks and pathways in implantation and early pregnancy in the mouse will be extended to in vitro cell cultures from human uterine endometrium undergoing decidualization. Hence, our specific aims are the following: (1) Generation of a conditional REA knockout mouse that can be used to study the functions of REA in reproductive tissues, (2) Characterization of the effects of conditional REA gene knockout on fertility and the uterine reproductive phenotype during early stages of pregnancy, using mouse ovary and embryo transplantation and artificial decidualization methods, (3) Analysis of gene networks and pathways regulated by REA in the wild type and REA knockout mouse uterus during implantation using a delayed implantation model, and (4) Functional analysis of REA and other corepressors in stromal cell cultures from human endometrium and characterization of hormone-regulated pathways and corepressor involvement in decidualization, for comparisons with their alterations in endometriosis. The results of our studies should delineate mechanisms and cellular pathways that underlie uterine receptivity and the processes of implantation and decidualization in early pregnancy, and advance our understanding of endometrial defects that reduce fertility in gynecologic disorders such as endometriosis. They should also aid in identifying new molecular diagnostic markers that might be useful in screening for uterine functional disorders and lead the way to future targeted drug therapies to optimize fertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD055787-05
Application #
8377597
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$233,582
Indirect Cost
$68,813
Name
University of Illinois Urbana-Champaign
Department
Type
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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Kaya Okur, Hatice S; Das, Amrita; Taylor, Robert N et al. (2016) Roles of Estrogen Receptor-α and the Coactivator MED1 During Human Endometrial Decidualization. Mol Endocrinol 30:302-13
Yu, Jie; Berga, Sarah L; Johnston-MacAnanny, Erika B et al. (2016) Endometrial Stromal Decidualization Responds Reversibly to Hormone Stimulation and Withdrawal. Endocrinology 157:2432-46
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Zhao, Yuechao; Chen, Yiru; Kuang, Ye et al. (2016) Multiple Beneficial Roles of Repressor of Estrogen Receptor Activity (REA) in Suppressing the Progression of Endometriosis. Endocrinology 157:900-12
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Zhao, Yuechao; Gong, Ping; Chen, Yiru et al. (2015) Dual suppression of estrogenic and inflammatory activities for targeting of endometriosis. Sci Transl Med 7:271ra9
Best, Monica W; Wu, Juanjuan; Pauli, Samuel A et al. (2015) A role for retinoids in human oocyte fertilization: regulation of connexin 43 by retinoic acid in cumulus granulosa cells. Mol Hum Reprod 21:527-34

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