Dissecting the role of RPLP1 in female reproductive tract pathologies

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Project Summary The endometrium is the inner lining of the uterus and is composed of endometrial epithelial and stromal cells among others. Endometrial epithelial-stromal communication is essential for successful reproduction. Perturbations in normal epithelial and stromal paracrine and autocrine signaling not only impairs successful reproduction but are also associated with endometrial pathologies such as endometriosis, adenomyosis and endometrial cancer. There is a growing body of evidence that indicates common alterations in the endometrial epithelial cells from women with these diseases, such as epithelial to mesenchymal transitions. Our recent observations further contribute to this field by identifying over-expression of the RPLP1 protein in endometrial epithelial cells from women with endometriosis, adenomyosis and endometrial cancer. Preliminary data in this application further suggest that RPLP1 over-expression may also influence expression of the progesterone receptor and progesterone signaling. This is an intriguing observation in that endometriosis, adenomyosis and endometrial cancer are all characterized by progesterone resistance. To expand upon these novel observations, we will test the specific hypothesis that over-expression of endometrial epithelial cell RPLP1 leads to alterations in endometrial epithelial cell molecular profiles consistent with augmented proliferation, migration and/or invasion and epithelial to mesenchymal transition (EMT) as well as progesterone signaling. To test this hypothesis, two specific aims are proposed both of which utilize a novel in vivo animal model for Rplp1 over-expression in endometrial epithelial cells. Specific Aim I will discern if over-expression of epithelial Rplp1 leads to impaired female fertility, development of uterine pathologies, and aberrant endometrial cell steroid signaling. Specific Aim II will interrogate cellular constituents and novel uterine molecular pathways resulting from epithelial Rplp1 over- expression. Collectively, the experiments proposed in this grant application will provide new insight into the role of RPLP1 in endometrial physiology and pathophysiology which may lead to the development of more-specific treatment modalities for diseases of the endometrium such as endometriosis, adenomyosis and/or endometrial cancer.