Cytoskeletal regulation of the Hippo and Notch1 signaling pathways in endometrial stromal cell decidualization and endometriosis

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PROJECT SUMMARY Endometrial stromal cell decidualization is critical to reproductive success. The decidualization process involves morphological and functional changes of endometrial stromal cells. The actin-myosin cytoskeleton contributes to changes in cell morphology and likely plays a role in the intracellular shuttling of proteins critical in decidualization. Decidualization is the terminal differentiation of human endometrial stromal cells in response to rising progesterone levels and is maintained throughout pregnancy by embryonic signals and progesterone. Defects in this process are associated with reproductive failure in diseases such as endometriosis. Endometriosis is characterized by endometrial-like tissue found at ectopic sites and the disease is associated with significant pelvic pain, infertility, and dysmenorrhea, but its pathophysiology remains elusive. The aim of this proposal is to understand the functional role of the cytoskeleton in the decidualization process and determine how this is aberrant in the stromal cells of women with endometriosis which may contribute to their infertility. The Hippo target homologs, YAP and TAZ, and Notch1 signaling are known to mediate the initiation of the decidualization response, but what regulates these pathways during decidualization remains unknown. Previous research has also shown that significant changes in the cytoskeleton are associated with endometrial stromal cell decidualization. In addition, cytoskeleton dynamics and Notch1 and YAP/TAZ signaling are dysregulated in endometriosis. We hypothesize that the cytoskeleton mediates the decidualization response and is defective in infertile women with endometriosis. To test our overall hypothesis in Aim 1 we will investigate direct actin-myosin cytoskeleton regulation of the Hippo/YAP/TAZ and NOTCH1 signaling pathways in the context of endometrial stromal cell decidualization and in Aim 2, we will determine how an altered cytoskeleton compromises decidualization in stromal cells from infertile women with endometriosis. The proposed studies will address cytoskeletal regulation of key molecular mechanisms that regulate stromal cell decidualization. These studies will greatly expand the technical expertise in cell and molecular biology of the applicant. These experiences combined with professional development supported by the sponsor, co-sponsor, and program will help the applicant to develop the skill set required to pursue a career in basic science research.