The overall objective of this proposal is to define the essential molecular mechanisms that underlie the role of COUP-TFII in the regulation of endometrial function in preparation of the uterus to support pregnancy and how alteration of these mechanisms results in endometrial dysfunction, such as endometriosis. During the last funding period, we have demonstrated, using genetically engineered mouse models, that COUP-TFII is critical in regulating the initiation of pregnancy by controlling the ability of the uterus to support embryo attachment, invasion, and the maintenance of pregnancy. COUP-TFII regulates these processes by controlling uterine epithelial cell sensitivity to estrogen, as well as, uterine stromal cell proliferation, vascularization, and differentiation by regulating Wnt and Epidermal Growth Factor (EGF) signaling pathways. Using primary human endometrial tissue, we have shown that this pathway is conserved in the human endometrium and COUP-TFII is critical for the ability of human endometrial stromal cells to differentiate in vitro. The goal of this proposal will be to investigate how COUP-TFII regulates endometrial epithelial ER signaling and stromal Wnt and EGFR signaling in the regulation of endometrial function and dysfunction. This will be accomplished by achieving the following aims: 1 .The importance of COUP-TFII regulation of endometrial epithelial E2 sensitivity in controlling uterine receptivity will be investigated. 2. The role of COUP-TFII in the regulation of human endometrial estrogen sensitivity will be determined. 3. The molecular mechanism by which COUP-TFII regulates the expression of target genes in human endometrial stromal cells will be investigated. 4. The role of EGFR in the ability of the PR-lhh-COUP-TFII axis to regulate endometrial function will be investigated. Accomplishment of these aims will define the molecular mechanisms regulating endometrial function and dysfunction.

Public Health Relevance

Infertility and diseases of the female reproductive tract, such as endometriosis are significant human health issues. The goal of this project is to use mouse models and primary human tissues to define the processes regulating uterine function and how these processes are disrupted in uterine disease.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD007495-40
Application #
8446120
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
40
Fiscal Year
2013
Total Cost
$218,115
Indirect Cost
$64,088
Name
Baylor College of Medicine
Department
Type
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Piyarathna, Danthasinghe Waduge Badrajee; Rajendiran, Thekkelnaycke M; Putluri, Vasanta et al. (2018) Distinct Lipidomic Landscapes Associated with Clinical Stages of Urothelial Cancer of the Bladder. Eur Urol Focus 4:907-915
Choi, Byung-Kwon; Dayaram, Tajhal; Parikh, Neha et al. (2018) Literature-based automated discovery of tumor suppressor p53 phosphorylation and inhibition by NEK2. Proc Natl Acad Sci U S A 115:10666-10671
Parikh, Neha; Shuck, Ryan L; Gagea, Mihai et al. (2018) Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene-induced lung tumors in aged mice. Aging Cell 17:
Kotlajich, Matthew V; Xia, Jun; Zhai, Yin et al. (2018) Fluorescent fusions of the N protein of phage Mu label DNA damage in living cells. DNA Repair (Amst) 72:86-92
Szafran, Adam T; Stossi, Fabio; Mancini, Maureen G et al. (2017) Characterizing properties of non-estrogenic substituted bisphenol analogs using high throughput microscopy and image analysis. PLoS One 12:e0180141
Ha, Kyungsoo; Ma, Chengxian; Lin, Han et al. (2017) The anaphase promoting complex impacts repair choice by protecting ubiquitin signalling at DNA damage sites. Nat Commun 8:15751
Roarty, K; Pfefferle, A D; Creighton, C J et al. (2017) Ror2-mediated alternative Wnt signaling regulates cell fate and adhesion during mammary tumor progression. Oncogene 36:5958-5968
Aagaard, Kjersti M; Lahon, Anismrita; Suter, Melissa A et al. (2017) Primary Human Placental Trophoblasts are Permissive for Zika Virus (ZIKV) Replication. Sci Rep 7:41389
Szafran, Adam T; Stephan, Cliff; Bolt, Michael et al. (2017) High-Content Screening Identifies Src Family Kinases as Potential Regulators of AR-V7 Expression and Androgen-Independent Cell Growth. Prostate 77:82-93
Tsai, Wei-Chih; Reineke, Lucas C; Jain, Antrix et al. (2017) Histone arginine demethylase JMJD6 is linked to stress granule assembly through demethylation of the stress granule-nucleating protein G3BP1. J Biol Chem 292:18886-18896

Showing the most recent 10 out of 159 publications