Even when the blastocyst develops normally, inadequate differentiation of stromal cells to decidual cells in the endometrium (termed decidualization) can lead to implantation failure or early embryo miscarriage. Although many of the cellular mechanisms that underpin steroid-hormone actions in endometrial physiology are well defined, a significant knowledge-gap exists concerning the coregulator and signaling pathways that control or mediate steroid-hormone responses in the decidualization process. This knowledge-gap is significant as without new mechanistic insights into this aspect of embryo implantation, the ability to diagnose and/or treat infertility based on a functionally impaired endometrium will not be realized. Recently, I identified GREB1 as a progesterone responsive gene and critical for the induction of progesterone molecular targets required for decidualization of primary human endometrial stromal cells in culture. Therefore, this finding implicates a coactivator role for GREB1 in this cellular process. In parallel studies, I also showed that GREB1 is required for estrogen-driven proliferation of endometrioma cells derived from endometriosis patients, indicating a separate role for GREB1 in estrogen-dependent endometriosis. Based on my preliminary observations, I hypothesize that the coactivator function of GREB1 is required both for progesterone-driven endometrial decidualization and for estrogen-dependent endometriosis progression. Therefore, my proposal plans to examine the dual role of GREB1 in endometrial function and dysfunction. The K99 phase will establish the in vivo role of GREB1 in normal endometrial responses to progesterone exposure using a recently engineered mouse model. These studies will transition into the R00 portion, which uses this model to define the pathogenic importance of GREB1 in estrogen-driven endometriosis. The R00 phase will also determine the molecular mechanism that underpins the coactivator function of GREB1 in progesterone-driven human endometrial decidualization. Combined with career development training, which will include mentoring, course work, and presentation opportunities, these studies will extend my training in endometrial physiology and pathophysiology to provide a strong foundation to launch an independent career in the reproductive sciences in near future.

Public Health Relevance

Embryo implantation failure is a significant (yet poorly understood) cause of female infertility, a critical reproductive health issue for women worldwide. To address this unmet clinical issue, this project will provide key mechanistic insight into the regulation of sex-steroid hormone action not only in the normal function of the endometrium but also in pathogenic processes that lead to endometriosis. Outcomes from this project will not only provide mechanistic insights on early embryo miscarriage but also lead into several lines of future work on endometrial disorders associated with infertility.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Eisenberg, Esther
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Washington University
Obstetrics & Gynecology
Schools of Medicine
Saint Louis
United States
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Michalski, Stephanie A; Chadchan, Sangappa B; Jungheim, Emily S et al. (2018) Isolation of Human Endometrial Stromal Cells for In Vitro Decidualization. J Vis Exp :
Szwarc, Maria M; Hai, Lan; Gibbons, William E et al. (2018) Human endometrial stromal cell decidualization requires transcriptional reprogramming by PLZF. Biol Reprod 98:15-27
Szwarc, Maria M; Hai, Lan; Gibbons, William E et al. (2018) Retinoid signaling controlled by SRC-2 in decidualization revealed by transcriptomics Reproduction 156:387-395
Szwarc, Maria M; Kommagani, Ramakrishna; Putluri, Vasanta et al. (2018) Steroid Receptor Coactivator-2 Controls the Pentose Phosphate Pathway through RPIA in Human Endometrial Cancer Cells. Sci Rep 8:13134
Szwarc, Maria M; Kommagani, Ramakrishna; Peavey, Mary C et al. (2017) A bioluminescence reporter mouse that monitors expression of constitutively active ?-catenin. PLoS One 12:e0173014
Camden, Alison J; Szwarc, Maria M; Chadchan, Sangappa B et al. (2017) Growth regulation by estrogen in breast cancer 1 (GREB1) is a novel progesterone-responsive gene required for human endometrial stromal decidualization. Mol Hum Reprod 23:646-653