Infertility and subfertility are pervasive problems in humans, and pregnancy loss is the most common complication of human gestation, with losses occurring most frequently in the first two weeks of gestation. Our long-range goal is to discover and understand the cellular and molecular mechanisms regulating uterine competency for pregnancy with a specific focus on uterine functions for blastocyst implantation in order to provide fundamental information useful for diagnosis, prevention and treatment of fertility problems. The receptive endometrium represents a temporary, but unique physiological state of the uterus when blastocyst growth and implantation is possible. Inadequate endometrial function, receptivity and decidualization negatively affect blastocyst implantation leading to pregnancy loss. Our central hypothesis is that endometrial glands and their secretions regulate endometrial receptivity, endometrial decidualization and blastocyst implantation. The goal of this proposal is to begin testing that hypothesis using a mouse model that lacks endometrial glands (conditional Foxa2 mutant).
Specific aims are to: (1) determine the impact of endometrial glands and their secretions on endometrial receptivity and stromal decidualization; and (2) interrogate the endometrial epithelial transcriptome and secretome of early pregnancy. The systems biology approach, utilizing functional genomics and discovery-based methods in combination with a mouse model lacking endometrial glands, is innovative and could lead to identification of novel biomarkers of endometrial receptivity and uterine competency for pregnancy. Successful completion of the proposed research will fill a substantial gap in our scientific knowledge and impact the fields of uterine and pregnancy biology.
Completion of the proposed research is expected to provide a better understanding of origins of infertility and pregnancy loss. The research should lead to new therapies to enhance pregnancy outcome in females conceiving naturally or via assisted reproduction technologies (ART). Translational outcomes include biomarkers of endometrial receptivity and function, which is of paramount importance for embryo/conceptus survival and growth during pregnancy in humans.
|Kelleher, Andrew M; Milano-Foster, Jessica; Behura, Susanta K et al. (2018) Uterine glands coordinate on-time embryo implantation and impact endometrial decidualization for pregnancy success. Nat Commun 9:2435|
|Kelleher, Andrew M; Peng, Wang; Pru, James K et al. (2017) Forkhead box a2 (FOXA2) is essential for uterine function and fertility. Proc Natl Acad Sci U S A 114:E1018-E1026|
|Kelleher, Andrew M; Burns, Gregory W; Behura, Susanta et al. (2016) Uterine glands impact uterine receptivity, luminal fluid homeostasis and blastocyst implantation. Sci Rep 6:38078|
|Spencer, Thomas E (2014) Biological roles of uterine glands in pregnancy. Semin Reprod Med 32:346-57|
|Filant, Justyna; Spencer, Thomas E (2014) Uterine glands: biological roles in conceptus implantation, uterine receptivity and decidualization. Int J Dev Biol 58:107-16|