Uterine receptivity is an ovarian hormone controlled transient state in which the uterus can accept an embryo to implant. Transformations in luminal endometrial epithelium (LE) mi- croenvironment are associated with the establishment of uterine receptivity. Dysregulated LE microenvironment during implantation window is implicated in defective uterine receptivity. A fundamental knowledge gap is what and how local factors mediate ovarian hormone signals to transform LE microenvironment upon the establishment of uterine receptivity. LPAR3, the third receptor for lysophosphatidic acid (LPA) implicated in uterine receptivity, is mainly ex- pressed in LE and deletion of Lpar3 leads to altered expression of genes involved in regulat-ing LE microenvironment in preimplantation day 3.5 uterus. Our long-term goal is to under- stand the molecular mechanism of uterine receptivity. The overall objective of this application, which is a step toward attaining our long-term goal, is to identify altered LE microenvironment and associated candidate genes in the Lpar3(-/-) uterus. The central hypothesis is that LPAR3 is a local factor regulating LE microenvironment via gene expression. This hypothesis is for- mulated based on our preliminary data obtained from Lpar3(-/-) mice. The rationale is that un- derstanding the role of LPAR3 in LE microenvironment will give us more insight into the mo- lecular mechanism of uterine receptivity. To achieve the goal of this application, two specific aims will be pursed.
Aim 1. Identify altered LE microenvironment in peri-implantation Lpar3(-/-) uterus, based on the working hypothesis that deletion of Lpar3 leads to an unfavorable LE microenvironment for implantation.
Aim 2. Determine expression of candidate genes asso- ciated with the altered LE microenvironment in peri-implantation Lpar3(-/-) LE, based on the working hypothesis that altered LE microenvironment is caused by altered gene transcription in Lpar3(-/-) LE. Scanning and transmission electron microscopy, realtime PCR, promoter ana- lyses, ChIP assay, and pharmacological approaches will be employed. The proposed re- search is significant because it is expected to decipher the molecular mechanism of how local factor LPAR3 regulates the expression of genes that can influence LE microenvironment thus uterine receptivity. The obtained knowledge will advance and expand our understanding of the molecular mechanism of uterine receptivity.
The proposed research is relevant to public health because defective uterine receptivity is a key factor for infertility and early pregnancy loss. This proposal aims to understand how LPAR3 regulates the expression of genes involved in the transformations of luminal endome- trial epithelium microenvironment to influence uterine receptivity. The understanding of the molecular mechanism in establishment of uterine receptivity will provide a foundation for drug discoveries to treat infertility and early pregnancy loss associated with defective uterine re- ceptivity.
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