Uterine receptivity, the ability of the uterus to accept embryo implantation, is dependent upon ovarian steroid signaling which coordinates the paracrine crosstalk between the epithelial and stromal compartments of the endometrium. The ovarian steroid Progesterone, P4, acting through its cognate receptor, Pgr (mouse), is critical in the regulation of the compartmental crosstalk. During pregnancy, Pgr is expressed in the uterine epithelial for a finite period prior to embryo attachment. In humans, alteration in the PGR signaling is associated with endometrial diseases, such as infertility, endometriosis, and endometrial cancer. Hyperstimulation of PGR is associated with pregnancy failure after in vitro fertilization and embryo transfer, IVF/ET. The goal of this proposal is to investigate the molecular mechanisms regulated by Pgr and how they function in the regulation of uterine receptivity and disease. Utilizing Chromatin Immunoprecipitation combined with whole genome sequencing, ChIP-Seq, we have identified the binding sites of Pgr in the murine genome and have identified the transcription factor Sox17 as a Pgr target and potential partner of Pgr in the regulation of uterine receptivity. The hypothesis of this proposal is that cell specific and temporl interactions of Pgr and Sox17 are critical for uterine receptivity and alterations in the expressio of Sox17 and Pgr will impair uterine function. This proposal will investigate the role of Sox17 in the regulation of mouse uterine function. We will then investigate the molecular interactions of Sox17 in the regulation of endometrial function. Finally, we will test the importance of the timing of Pgr regulated signaling in mouse uterine receptivity. Completion of the aims of this proposal will define the role of PR in the regulation of endometrial function and determine the functional interactions of PR with other transcription factors in the regulation of endometrial gene expression and function. This proposal will also determine the importance or the temporal expression of PR in the uterus. Understanding how altered expression of PR disrupts uterine function is critical in understanding how the uterus response to endocrine therapy.

Public Health Relevance

Diseases of the uterus, such as infertility, endometriosis and endometrial cancer are a result of altered responses of the uterus to progesterone. The goal of this proposal is to investigate how the hormone progesterone, acting though its receptor regulates the ability of the uterus to support embryo implantation and control processes that prevent diseases, such as endometriosis and endometrial cancer.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD042311-11A1
Application #
8755743
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Yoshinaga, Koji
Project Start
2002-04-01
Project End
2019-04-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
11
Fiscal Year
2014
Total Cost
$326,986
Indirect Cost
$119,486
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

Showing the most recent 10 out of 48 publications