The overall objective of this proposal is to define the essential molecular mechanisms that underlie the preparation of the uterus to support embryo implantation. Specifically, this proposal will investigate the molecular pathways regulated by the ovarian steroid hormone, progesterone (P4), in the pre-implantation uterus. P4 acting through its cognate nuclear receptor, the progesterone receptor (PR), regulates the transcription of genes which coordinate the ability of the uterus to support embryo implantation and fetal development. Alterations in P4 signaling are associated with endometrial diseases, such as infertility, endometriosis and endometrial cancer. During the last funding period, we have demonstrated that conditional ablation of Ihh in the murine uterus results in loss of stroma cell proliferation, vascularization, and differentiation. This phenotype resulted in the inability of the uterus to undergo the post-implantation decidual reaction. In addition to the regulation of endometrial stroma function, inactivation of Ihh signaling interfered with the ability of the endometrial epithelium to support embryo attachment and invasion. We have preliminary data illustrating that ablation of Ihh results in an increase in the expression of Estrogen Receptor alpha (ER1) and estrogen (E2) regulated genes in the endometrial epithelium. The first goal of this application is to test the hypothesis that the increased E2 sensitivity in the uterine epithelium is the cause of the implantation defect due to loss of Ihh expression. We will then further investigate the interaction of the P4 regulated Ihh pathway with E2 signaling by determining the regulation by and role of Ihh in the Leukemia Inhibitory Factor (Lif) signaling axis, an E2 regulated pathway that is critical for normal implantation. Finally, given the importance of the PR-Ihh axis in the regulation of uterine function, we will define the molecular mechanism by which PR regulates the expression of Ihh. This will be accomplished in three specific aims. (1) The physiological significance of the increased E2 signaling in the endometrial epithelium after ablation of Ihh on uterine receptivity will be investigated. (2) The interaction of the Ihh signaling axis with that of the E2 regulated Leukemia Inhibitory Factor (Lif) signaling axis in the preparation the uterus for embryo implantation will be identified. (3) The molecular mechanism by which endometrial epithelial PR regulates the expression of Ihh and uterine function will be defined in vivo. The completion of the aims of this proposal will define the role of P4 regulated pathways in the regulation of uterine epithelial function.

Public Health Relevance

Infertility, endometriosis, and endometrial cancer have a large affect on women's health. This project will determine the role the steroid, progesterone has on these diseases.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD042311-07
Application #
7752829
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Yoshinaga, Koji
Project Start
2008-01-01
Project End
2013-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
7
Fiscal Year
2010
Total Cost
$307,089
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Peavey, Mary C; Reynolds, Corey L; Szwarc, Maria M et al. (2017) Three-Dimensional High-Frequency Ultrasonography for Early Detection and Characterization of Embryo Implantation Site Development in the Mouse. PLoS One 12:e0169312
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
Wetendorf, Margeaux; Wu, San-Pin; Wang, Xiaoqiu et al. (2017) Decreased epithelial progesterone receptor A at the window of receptivity is required for preparation of the endometrium for embryo attachment. Biol Reprod 96:313-326
Shen, Jieli; Yao, Lijing; Lin, Yvonne G et al. (2016) Glucose-regulated protein 94 deficiency induces squamous cell metaplasia and suppresses PTEN-null driven endometrial epithelial tumor development. Oncotarget 7:14885-97
Mehta, Fabiola F; Son, Jieun; Hewitt, Sylvia C et al. (2016) Distinct functions and regulation of epithelial progesterone receptor in the mouse cervix, vagina, and uterus. Oncotarget 7:17455-67
Xiao, Lijuan; Feng, Qin; Zhang, Zheng et al. (2016) The essential role of GATA transcription factors in adult murine prostate. Oncotarget 7:47891-47903
Lee, I I; Maniar, K; Lydon, J P et al. (2016) Akt regulates progesterone receptor B-dependent transcription and angiogenesis in endometrial cancer cells. Oncogene 35:5191-201
Vasquez, Yasmin M; Wu, San-Pin; Anderson, Matthew L et al. (2016) Endometrial Expression of Steroidogenic Factor 1 Promotes Cystic Glandular Morphogenesis. Mol Endocrinol 30:518-32
Rubel, Cory A; Wu, San-Pin; Lin, Lin et al. (2016) A Gata2-Dependent Transcription Network Regulates Uterine Progesterone Responsiveness and Endometrial Function. Cell Rep 17:1414-1425
Kim, Yeon Sun; Kim, Hye-Ryun; Kim, Hyongbum et al. (2016) Deficiency in DGCR8-dependent canonical microRNAs causes infertility due to multiple abnormalities during uterine development in mice. Sci Rep 6:20242

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