Diagnosis and Treatment of Endometriosis: A Translational Approach

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Project 1 (Young) Diagnosis and Treatment of Endometriosis: A Translational Approach ABSTRACT The Collaborative Center to Develop Improved Diagnostic and Therapeutic Approaches to Endometriosis has the overarching goal of developing advanced tools and insights for improved understanding of the pathophysiology of endometriosis. We pursue this goal to enhance the diagnosis, assessment, and treatment of women suffering from this common and devastating disease. Progress in understanding the etiology and pathophysiology of endometriosis has been significantly compromised by limits to disease assessment, and current therapeutic approaches prevent fertility and are minimally effective. The dependence on surgical assessment delays diagnosis and limits clinicians and researchers from confirming endometriosis lesion recurrence or response to therapies. Thus, a better paradigm is needed to scientifically address this disorder. Chronic inflammation underlies both infertility and pain in the disease. While resolution of inflammation throughout the body requires specialized pro-resolving mediators (SPMs), including derivatives of arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, these mediators have not been closely examined in women with endometriosis. Some SPMs require SIRT1, a histone deacetylase that epigenetically regulates many disease processes and is overexpressed in the eutopic endometrium of individuals with endometriosis in humans, baboons, rhesus macaques, and mouse endometrium. However, inflammation persists in endometriosis, suggesting that SIRT1 induction of SPM resolving activity is compromised. Our preliminary data indicate that a change in receptor expression results in a shift from anti-inflammatory to pro-inflammatory actions of SPMs. Therefore, SIRT1 and SPMs may represent novel therapeutic targets for endometriosis. Our specific aims address the gaps in endometriosis diagnosis and therapy as follows: In Aim 1, we approach the problem of diagnosis by refining a novel imaging technique that takes advantage of both steroid hormone expression in endometriosis lesions and the associated inflammation: we propose imaging endometriosis using a progestin-based tracer 21-[18F]fluoro-furanyl-nor-progesterone (FFNP) for positron emission tomography (PET) combined with simultaneous gadolinium(Gd)-contrast, magnetic resonance imaging (GMRI), to allow anatomic localization of endometriosis lesions and highlight areas of inflammation. In Aim 2, we directly address the issue of treatment by investigating why endometriosis-related inflammation is not resolved by SPMs, including evaluation of post-translational modifications of SIRT1 and expression of SPM biosynthetic enzymes and receptors in women with and without endometriosis; and the correlation of these parameters with inflammation and metabolic alterations in human and non-human primate tissue. This project exhibits clear synergy with both Project 2 (Jeong and Lessey) and Project 3 (Slayden) and provides cross-species and cross-model comparisons between humans, nonhuman primates, and mouse models, aided by the Comparative Genomics and Bioinformatics (CGB) Core.