This application requests funding for the establishment of a Specialized Cooperative Center in Reproductive Research at Yale and Vanderbilt Universities to be named """"""""The Center for Endometrial Biology and Endometriosis."""""""" Disorders of the endometrium and endometriosis result in significant morbidity including infertility, abnormal uterine bleeding, pelvic pain and dysmenorrhea. Endometriosis affects 10-15% of reproductive aged women and up to 50% of women with infertility. Endometrial disorders are a common problem with wide-spread public health implications. Despite the prevalence of these disorders, little progress had been made in understanding these conditions or their treatment. Therapy relies on hormonal manipulation and is fraught with side effects and treatment failures. The central theme of this application is discovery of novel mechanisms and therapeutic targets for endometrial disease and endometriosis. Each project, supported by preliminary data, hypothesizes a novel regulatory mechanism involved in the etiology or growth of this tissue, as well as suggests or tests novel therapies. The Center is collaborative and supported by three cores. Five interactive research projects address the central elements of this hypothesis. Project I will characterize the engraftment of endometrium and endometriosis with transdifferentiated bone marrow-derived stem cells. This Project will determine the extent to which bone marrow gives rise to the endometrium, the underlying mechanisms and functional consequences. Project II will explore the role of tissue factor in regulation of endometrial growth. Macrophage derived tissue factor contributes to endometrial growth and can be blocked by a novel immunoconjugated molecule (ICON) that targets tissue factor. Project III will look at failure of progesterone action in endometriosis due to disruption of a novel pathway involving epithelial- dominant cell-cell communication and TGF beta as well as retinoid signaling. Project IV will further determine the role of the mevalonate pathway on endometrial stromal cell growth and tests the novel use of statins as inhibitors of endometrial growth. Project V is a pilot project that explores the chemokines that recruit macrophages in endometriosis and tests the effects of traditional and novel treatments discovered here on signal transduction. The Center also contains three Cores. An Administrative Core, a Cell and Tissue Core and Mouse Modeling Core will be used by each of the investigators and complete a comprehensive Center.
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