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.