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 #
5R01HD042311-10
Application #
8403522
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Yoshinaga, Koji
Project Start
2008-01-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
10
Fiscal Year
2013
Total Cost
$276,893
Indirect Cost
$96,507
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
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
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
Kommagani, Ramakrishna; Szwarc, Maria M; Vasquez, Yasmin M et al. (2016) The Promyelocytic Leukemia Zinc Finger Transcription Factor Is Critical for Human Endometrial Stromal Cell Decidualization. PLoS Genet 12:e1005937
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
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
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
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
Monsivais, Diana; Clementi, Caterina; Peng, Jia et al. (2016) Uterine ALK3 is essential during the window of implantation. Proc Natl Acad Sci U S A 113:E387-95
Mazur, Erik C; Vasquez, Yasmin M; Li, Xilong et al. (2015) Progesterone receptor transcriptome and cistrome in decidualized human endometrial stromal cells. Endocrinology 156:2239-53
Han, Sang Jun; Jung, Sung Yun; Wu, San-Pin et al. (2015) Estrogen Receptor β Modulates Apoptosis Complexes and the Inflammasome to Drive the Pathogenesis of Endometriosis. Cell 163:960-74

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