Prostaglandin E2 Signaling in Growth and Pains of Endometriosis

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DESCRIPTION (provided by applicant): Endometriosis is an inflammatory disease characterized by the presence of functional endometrium outside the uterine cavity. The major two symptoms are intolerable pelvic pain and infertility. Prostaglandin E2 (PGE2) plays important roles in the pathogenesis of endometriosis. PGE2 is the principal mediator in inflammation and pain hypersensitivity. Inhibition of PGE2 biosynthesis using NSAIDs and COX-2 inhibitors has emerged as the main class analgesics. However, clinical use of NSAIDs produces unwanted side effects such as gastric erosion, ulceration, and hemorrhage, and prolonged use of COX-2-selective inhibitors confers a risk for myocardial infarction and stroke. PGE2 produced at the site of inflammation acts on the nociceptors of peripheral terminals through EP1, EP2, EP3, and EP4 receptors by integrating multiple cell signaling pathways. Selective inhibition of PGE2 signaling as therapeutic targets down-stream of COX-2 may provide an opportunity to inhibit pro-nociceptive actions of PGE2 in the pathogenesis of endometriosis. Our long-term goal is to understand molecular and cellular aspects of PGE2 in the pathogenesis and pain of endometriosis with the aim of identifying PGE2receptors as non-steroidal targets for the treatment of endometriosis. The objective of this application is to understand PGE2 signaling in growth and pain of endometriosis. The central hypothesis is that selective inhibition of prostaglandin E2 signaling decreases pain of endometriosis through inhibition of growth of endometriotic cells and development of nociceptive mechanisms. Specific Aim 1 will determine the effects of systemic blockade of EP2 and EP4 receptors on growth, innervations, and pain of endometriosis. Specific Aim-2 will determine molecular mechanisms of through which cell specific knock-down of EP2 and EP4 in endometriotic epithelial and stromal cells inhibits development of innervations and nociceptive mechanisms of endometriosis. Effects of selective inhibition of EP2 and EP4 on growth, innervations, and pain of endometriosis will be determined using genomic, pharmacological, molecular, cellular, biochemical, microscopy, and bioimaging approaches, and xenograft Rag23(c) mice and pain behavior animal models. The proposed work is innovative: (i) because it capitalizes on a new means of identifying PGE2 signaling in the pathogenesis of endometriosis and induction of endometriosis pain, and (ii) expected to decrease pain of endometriosis through inhibition of growth of endometriotic cells, innervations of endometriosis, and development of peripheral and central nociceptive mechanisms. This highly significant advancement in our understanding of endometriosis will provide the knowledge needed to translate selective inhibition of EP2 and EP4 into clinical application as a potential novel non-steroidal therapy for endometriosis in women. In addition, the expected results will fill the substantial gap in the current knowledge of the pathogenesis of endometriosis and perception of endometriosis pain. This is a R21 application addresses the mission of NIH/NICHD on women's reproduction health. PUBLIC HEALTH RELEVANCE: The objectives of the proposed research are to determine molecular and cellular mechanisms through which selective inhibition of prostaglandin E2 (PGE2) receptors EP2 and EP4 inhibits growth of endometriosis and endometriosis-induced pain and to develop EP2 and EP4 inhibitors as new non-steroidal targets for the treatment of endometriosis in women. The expected outcomes of this project are that selective inhibition of EP2 and EP4-mediated PGE2 signaling will decrease growth and pain of endometriosis and fill the substantial gap in the current knowledge of the pathogenesis of endometriosis and perception of endometriosis pain. This highly significant advancement in our understanding of endometriosis will provide the knowledge needed to translate selective inhibition of EP2 and EP4 into clinical application as a potential novel non-steroidal therapy for endometriosis in women.