Implantation is an important part of early human develoment, because abnormalities in this process can lead to miscarriage, infertility, and pregnancy disorders, including fetal growth restriction and pre-eclampsia. Successful implantation requires estradiol (E2)-induced endometrial cellular growth and progesterone (P)- induced differentiation (decidualization). IGF-II is a major cytoytophoblast (CTB) product that regulates maternal decidual modulators of CTB invasion. We have recently found that IGF-II and other CTB products also elicit an immune phenotype in decidual fibroblasts that is dependent on the extent of P action on these cells. For example, the chemokine and angiogenic factor CXCL1 (GRO1) is up-regulated in response to IGF-II action on decidualized (but not non-decidualized) stromal fibroblasts. Its cognate receptor, CXCL2, is abundantly expressed in CTB, suggesting an important role for CXCL1/CXCL2 pair in maternal-trophoblast interactions. Limited P response in endometrium is a characteristic of women with endometriosis, a gynecologic disorder associated with infertility and poor pregnancy outcome, believed to be due, in large part, to P-resistance in the endometrium. We hypothesize that incomplete P action on endometrial stromal fibroblasts compromises their paracrine immune response to invading CTBs and may predispose women with this disorder to infertility and poor pregnancy outcome.
Our specific aims are:
Aim 1. To elucidate mechanisms underlying P-resistance in endometrial stromal fibroblasts from women with endometriosis, with a focus on P-regulated genes and FOXO1 A, a key determinant of stromal fibroblast cell fate.
Aim 2. To elucidate decidua-trophoblast interactions and IGF-II signaling pathways in the immune response of endometrial stromal fibroblasts in women with and without endometriosis.
Aim 3. To determine whether CXCL1, produced by the decidualized .stromal fibroblast in response to the invading trophoblast, affects human trophoblast proliferation, differentiation/invasion and acquisition of a vascular phenotype. Successful completion of the proposed experiments promises to strengthen our understanding of endometrial-based infertility and poor pregnancy outcomes in women with endometriosis and to contribute to the development of novel diagnostics and therapeutics associated with this disorder. Our participation in this Center is greatly enriched by our interactions with all investigators and access to its valuable core facilities.
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