Defective uterine receptivity, including delayed uterine receptivity and non-receptive endometrium, is the key maternal factor for infertility and early pregnancy loss. The molecular mechanism of how a uterus transforms into a receptive state for embryo implantation is not well understood. It is well recognized that progesterone receptor (PR)-mediated hormonal signaling is essential for the establishment of uterine receptivity in all mammals studied. PR has dynamic spatiotemporal expression patterns in the peri-implantation uterus. The disappearance of PR from uterine luminal (LE) and glandular epithelium is associated with the establishment of uterine receptivity. Failure of such down regulation of PR in uterine epithelium during the expected "implantation window" is associated with defective uterine receptivity. LPA3 (LPAR3/EDG7) is the third receptor for lysophosphatidic acid. Down regulation of uterine LPA3 is implicated in defective uterine receptivity in endometriosis patients and deletion of Lpar3 in mice leads to delayed uterine receptivity. Sustained PR expression in LE is detected in the non-receptive day 4.5 Lpar3(-/-) mouse uterus (normal implantation: ~day 4.0 in mouse). How the sustained PR expression in LE during the expected "implantation window" blocks uterine receptivity and how PR-mediated hormonal signaling interacts with local targets to control uterine receptivity remain as significant knowledge gaps. The long-term goal is to understand the molecular mechanism of uterine receptivity thus help overcome infertility and early pregnancy loss associated with defective uterine receptivity. The overall objective of this application is to fill the mentioned knowledge gaps, specifically the significance of sustained PR expression in LE and the interplay between PR and LPA3 in LE. The central hypothesis, formulated based on supportive preliminary data, is that PR interplays with LPA3 to coordinately regulate uterine receptivity. The rationale is that understanding the significance of PR in LE and its interplay with LPA3 will provide more insight into the molecular mechanism of uterine receptivity. To achieve the goal of this application, three specific aims will be pursed.
Aim 1. Determine molecular pathways dysregulated in LE with sustained PR expression, based on the working hypothesis that sustained PR expression in LE dysregulates genes/molecular pathways leading to a non-receptive uterus.
Aim 2. Determine interplay between PR and LPA3 in LE, based on the working hypo- thesis that PR and LPA3 mutually regulate each other in LE for the establishment of uterine receptivity.
Aim 3. Determine role of LPA3 in regulating molecular pathways in preimplantation day 3. 5 endometrium, based on the working hypothesis that LPA3 regulates its uterine target genes to influence uterine receptivity directly and/or via PR in LE. Laser microdissection, gene profiling, immunoblotting, ChIP assay, and immonoprecipitation are among the approaches that will be employed. The proposed work is significant because understanding the molecular mechanism of uterine receptivity is critical for developing diagnostic and therapeutic approaches to detect and treat infertility and early pregnancy loss associated with defective uterine receptivity.

Public Health Relevance

The proposed research is relevant to public health because defective uterine receptivity is a key factor for two important public health problems, infertility and early pregnancy loss. This proposal aims to decipher how a local factor LPA3 interplays with progesterone receptor in uterine luminal epithelium to control uterine receptivity. The understanding of the molecular mechanism in establishment of uterine receptivity will provide the foundation for drug discoveries to treat infertility and early pregnancy loss associated with defective uterine receptivity.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Yoshinaga, Koji
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University of Georgia
Schools of Veterinary Medicine
United States
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