Endometriosis results from extrauterine endometrial implants that cause pelvic adhesions, bleeding, infertility, and pain. Long-term survival of endometriotic implants is associated with marked local inflammation, vigorous angiogenesis and over-expression of tissue factor (TF). In a number of malignant and inflammatory states, TF bound to factor Vila, activates the type-2 protease activated receptor (PAR-2) to upregulate the expression of inflammatory cytokines, matrix metalloproteinases (MMP) and vascular endothelial growth factor (VEGF) to promote cell invasion and angiogenesis. Novel Preliminary Results form the basis of our hypothesis that nidation, growth and angiogenesis of endometriotic tissue results from enhanced TF expression in endometrial cells and infiltrating macrophages. Subsequent binding of factor VII to TF activates PAR-2 to induce expression of angiogenic, proteolytic and inflammatory mediators. The latter, in turn, induce expression of PAR-2 as well as angiogenic factor receptors in adjacent endothelial cells to generate a potent angiogenic response. A novel immunoconjugate molecule (ICON) comprised of two mutated factor VII domains and an IgG Fc effector domain, targets TF while also recruiting activated Natural Killer (NK) cells. Preliminary Results also demonstrate that ICON blocks the growth and angiogenesis in a TF-expressing human endometrial epithelial cell line transplanted into severe combined immunodeficient mice (SCID). Given the integral importance of over-expressed TF in the nidation and growth of endometriotic implants, we posit that ICON treatment will eradicate endometriotic implants. To test these hypotheses we propose the following Specific Aims: 1) To characterize the expression and localization of TF and PAR-2 in eutopic and ectopic endometrium from endometriosis patients;2) To assess the molecular pathway(s) of TF/Vlla/PAR-2 signaling in endometrial epithelial and stromal cells, and macrophages as well as the effects of such signaling on endothelial cell migration, proliferation, tube formation and apoptosis;and 3) to determine if treatment with ICON eradicates endometriotic implants in a murine model. These studies examine an original pathogenic model to account for the survival and proliferation of endometriotic implants and evaluate a novel, non-toxic therapy that could eradicate endometriotic implants.
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