The sex steroid hormones, estrogen and progesterone, via their cognate receptors, play critical roles inuterine receptivity, implantation, and decidualization, enabling the effective establishment and maintenanceof early pregnancy. The action of estrogens through the estrogen receptor (ER) are critically dependent oncoregulator partner proteins, and we have shown that the ER-selective corepressor REA (for Represser ofEstrogen receptor Activity) serves as a brake on estrogen activities in the uterus and is important in embryodevelopment, uterine function and fertility. Further, aromatase expression and locally produced estrogen inthe early pregnancy uterus is not only required for implantation, but also critically regulates thedecidualization program. In addition, our recent findings reveal REA abundance is strikingly reduced inendometriosis vs. normal human endometrium. Thus, our goals in this project are to elucidate the role ofREA using a conditional REA knockout mouse we are generating, with which we can study the effects ofconditional deletion of this corepressor on fertility and the uterine reproductive phenotype during early stagesof 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 beextended 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 canbe used to study the functions of REA in reproductive tissues, (2) Characterization of the effects ofconditional REA gene knockout on fertility and the uterine reproductive phenotype during early stages ofpregnancy, 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 uterusduring implantation using a delayed implantation model, and (4) Functional analysis of REA and othercorepressors in stromal cell cultures from human endometrium and characterization of hormone-regulatedpathways and corepressor involvement in decidualization, for comparisons with their alterations inendometriosis.The results of our studies should delineate mechanisms and cellular pathways that underlie uterinereceptivity and the processes of implantation and decidualization in early pregnancy, and advance ourunderstanding 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 foruterine functional disorders and lead the way to future targeted drug therapies to optimize fertility.
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