This application requests funds to establish a Specialized Cooperative Center in Reproduction Research focused on the theme """"""""Uterine Biology and the Pathophysiology of Endometriosis"""""""". Endometriosis is a common gynecologic disorder associated with dysmenorrhea, pelvic pain and reduced fertility affecting 10-15% of all women and up to 50% of women with infertility. We will apply state-of-the-art cellular and molecular biology techniques using human tissues and animal models to examine key cellular mechanisms by which endometriosis is initiated and progresses. Most cases of endometriosis can be attributed to ectopic implantation of fragments of endometrium entering the peritoneal cavity following reflex menstruation. Our central hypothesis is that steroids, acting through local cytokines and growth factors, co-regulate essential endometrial proteins which mediate the adhesion, invasive implantation and the inflammatory response that accompanies the ectopic growth of endometrium. Immune cytokines can disrupt the normal regulation of these proteins, contribute further to the disease process. We have designed three, interactive research projects to address the central elements of our hypothesis. Project I examines the control of matrix metalloproteinases, enzymes essential for mediating the invasive establishment of ectopic I examines the control of matrix metalloproteinases, enzymes essential for mediating the invasive establishment of ectopic sites of human endometrium within the peritoneal cavity. This project also examines the consequences of cytokine-mediated disruption of the expression of these enzymes using human tissue in a nude mouse model. Project II examines the regulations of RANTES, a potent inflammatory chemokine capable of activating immune cells and disrupting gene regulation at implant sites of endometriosis. This project will also utilize human tissues and the nude mouse model to examine RANTES expression in vivo. Project III examines a unique family of proteins, metalloproteinase/disintegrins, which may be important for the initial epithelial cell-cell adhesion required for invasion of endometrial fragments into the peritoneal wall. These molecules have been linked to ovo-implantation processes and appear to be regulated by both steroids and inflammatory cytokines. The Center will include administrative, morphology and molecular biology cores to support all research project. Directors of each project and core reside at Vanderbilt University except for the director of Project II who resides at the University of California, San Francisco.
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