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 #
5U54HD007495-39
Application #
8375885
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
39
Fiscal Year
2012
Total Cost
$226,012
Indirect Cost
$66,372
Name
Baylor College of Medicine
Department
Type
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Lloyd, Richard E (2016) Enterovirus Control of Translation and RNA Granule Stress Responses. Viruses 8:93
Ren, Yi A; Liu, Zhilin; Mullany, Lisa K et al. (2016) Growth Arrest Specific-1 (GAS1) Is a C/EBP Target Gene That Functions in Ovulation and Corpus Luteum Formation in Mice. Biol Reprod 94:44
Toneff, M J; Sreekumar, A; Tinnirello, A et al. (2016) The Z-cad dual fluorescent sensor detects dynamic changes between the epithelial and mesenchymal cellular states. BMC Biol 14:47
Trial, JoAnn; Cieslik, Katarzyna A; Entman, Mark L (2016) Phosphocholine-containing ligands direct CRP induction of M2 macrophage polarization independent of T cell polarization: Implication for chronic inflammatory states. Immun Inflamm Dis 4:274-88
Giudice, Jimena; Loehr, James A; Rodney, George G et al. (2016) Alternative Splicing of Four Trafficking Genes Regulates Myofiber Structure and Skeletal Muscle Physiology. Cell Rep 17:1923-1933
Matatall, Katie A; Jeong, Mira; Chen, Siyi et al. (2016) Chronic Infection Depletes Hematopoietic Stem Cells through Stress-Induced Terminal Differentiation. Cell Rep 17:2584-2595
McConnell, Kellie I; Shamsudeen, Sabeel; Meraz, Ismail M et al. (2016) Reduced Cationic Nanoparticle Cytotoxicity Based on Serum Masking of Surface Potential. J Biomed Nanotechnol 12:154-64
Han, Sang Jun; Begum, Khurshida; Foulds, Charles E et al. (2016) The Dual Estrogen Receptor α Inhibitory Effects of the Tissue-Selective Estrogen Complex for Endometrial and Breast Safety. Mol Pharmacol 89:14-26
Huq, Redwan; Samuel, Errol L G; Sikkema, William K A et al. (2016) Preferential uptake of antioxidant carbon nanoparticles by T lymphocytes for immunomodulation. Sci Rep 6:33808
Szafran, Adam T; Mancini, Maureen G; Nickerson, Jeffrey A et al. (2016) Use of HCA in subproteome-immunization and screening of hybridoma supernatants to define distinct antibody binding patterns. Methods 96:75-84

Showing the most recent 10 out of 129 publications