The overall objective of this U54 application is to characterize, at molecular and cellular levels, the hormonal pathways that regulate embryo implantation and fertility. Failure of the fertilized embryo to implant into the endometrium is a major cause of infertility. Following its initial attachment to the uterine epithelium, the embryo invades the endometrial stroma, which then undergoes extensive differentiation and remodeling, known as decidualization. Implantation and decidualization are complex processes driven by a cascade of signaling events regulated by the steroid hormones estrogen and progesterone. The central hypothesis of this research program is that defects in these hormonal signaling pathways lead to improper uterine receptivity, decidualization and early pregnancy loss. DNA microarray-based gene expression profiling and receptor-coregulator analyses have revealed novel steroid-regulated pathways, providing important insights into the cellular mechanisms by which implantation is controlled. Combination of this new knowledge with functional analysis in gene knockout mouse models will provide a blueprint of the molecular networks that mediate the hormonal regulation of this process. Extension of these analyses to endometrial tissues obtained from normal women as well as those with endometriosis, a common gynecologic disorder associated with reduced fertility, will provide the important translational component of this research. The program is comprised of four complementary, synergistic projects: (1) Role of C/EBP beta in Uterine Decidualization and Implantation, (2) Nuclear Receptor Co-regulators in Implantation and Uterine Function, (3) Regulation of Stromal Differentiation and Implantation by the BMP2 Pathway, and (4) Endometriosis as a Clinical Model of Predecidual Dysfunction. Investigators will be aided by an Administrative Core that will oversee inter-project interactions and data sharing, and a Microscopy Core that will provide gene and protein expression analyses in cells and tissues. In summary, the results of our studies should improve understanding of the mechanisms and cellular pathways that control implantation and help identify factors that underlie infertility in women with endometriosis. They should also aid in developing new molecular diagnostic tools for screening endometrial dysfunction and enable targeted therapeutic strategies for the treatment of infertility.

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 #
8254321
Study Section
Special Emphasis Panel (ZHD1-DSR-L (54))
Program Officer
De Paolo, Louis V
Project Start
2008-04-07
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$1,318,595
Indirect Cost
$411,084
Name
University of Illinois Urbana-Champaign
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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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
Guzzo, Mathilde; Agrebi, Rym; Espinosa, Leon et al. (2015) Evolution and Design Governing Signal Precision and Amplification in a Bacterial Chemosensory Pathway. PLoS Genet 11:e1005460
Taylor, Robert N; Kane, Maureen A; Sidell, Neil (2015) Pathogenesis of Endometriosis: Roles of Retinoids and Inflammatory Pathways. Semin Reprod Med 33:246-56
Kaya, Hatice S; Hantak, Alison M; Stubbs, Lisa J et al. (2015) Roles of progesterone receptor A and B isoforms during human endometrial decidualization. Mol Endocrinol 29:882-95
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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