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.
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.
|Large, Michael J; Wetendorf, Margeaux; Lanz, Rainer B et al. (2014) The epidermal growth factor receptor critically regulates endometrial function during early pregnancy. PLoS Genet 10:e1004451|
|Wetendorf, Margeaux; DeMayo, Francesco J (2014) Progesterone receptor signaling in the initiation of pregnancy and preservation of a healthy uterus. Int J Dev Biol 58:95-106|
|Hewitt, Sylvia C; Li, Leping; Grimm, Sara A et al. (2014) Novel DNA motif binding activity observed in vivo with an estrogen receptor ? mutant mouse. Mol Endocrinol 28:899-911|
|Kommagani, Ramakrishna; Szwarc, Maria M; Kovanci, Ertug et al. (2014) A murine uterine transcriptome, responsive to steroid receptor coactivator-2, reveals transcription factor 23 as essential for decidualization of human endometrial stromal cells. Biol Reprod 90:75|
|Clementi, Caterina; Tripurani, Swamy K; Large, Michael J et al. (2013) Activin-like kinase 2 functions in peri-implantation uterine signaling in mice and humans. PLoS Genet 9:e1003863|
|Vasquez, Y M; DeMayo, F J (2013) Role of nuclear receptors in blastocyst implantation. Semin Cell Dev Biol 24:724-35|
|Nagashima, Takashi; Li, Qinglei; Clementi, Caterina et al. (2013) BMPR2 is required for postimplantation uterine function and pregnancy maintenance. J Clin Invest 123:2539-50|
|Wetendorf, Margeaux; Demayo, Francesco J (2012) The progesterone receptor regulates implantation, decidualization, and glandular development via a complex paracrine signaling network. Mol Cell Endocrinol 357:108-18|
|Afshar, Yalda; Jeong, Jae-Wook; Roqueiro, Damian et al. (2012) Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse. FASEB J 26:282-94|
|Franco, Heather L; Rubel, Cory A; Large, Michael J et al. (2012) Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function. FASEB J 26:1218-27|
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