Imaging and treatment of endometriosis in nonhuman primates

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Project 3: Imaging and treatment of endometriosis in nonhuman primates SUMMARY/ABSTRACT The overarching goal of this P01 Center is to advance our understanding of the pathophysiology of endometriosis in order to improve the diagnosis and treatment of the disease in women. Endometriosis is a painful disorder of women and nonhuman primates (NHPs) in which endometrium-like tissues form estrogen-dependent lesions outside the uterus. There is currently no cure; all approved therapies target estrogen (E2) action to manage symptoms, which is of limited use in reproductive-age women due to unwanted side effects. Macaques provide excellent preclinical models for testing novel therapies that have not been fully vetted for clinical trials. However, no reliable methods exist to detect early-stage disease in either women or monkeys, and improved diagnostic approaches are needed to evaluate new therapies. Our premise is that endometriotic cell metabolism is a novel target for improved therapies for the disease. This premise emanates, in part, from studies that have revealed that consumption of an obesogenic "western-style" diet (WSD) combined with testosterone (T) treatment increases the rate and severity of endometriosis in macaques. Furthermore, a key feature of endometriotic lesions is the presentation of chronic peritoneal inflammation. Endometrial Sirtuin 1 (SIRT1) has been reported as a biomarker of endometriosis. SIRT 1 mediates endometrial progesterone resistance associated with endometriosis-induced infertility. Moreover, SIRT1 is a protein deacetylase enzyme that functions as a metabolic sensor, regulating mitochondrial respiration and aerobic glycolysis. Increased understanding of the role of SIRT1 and other inflammatory and metabolic markers may help to identify more reliable methods of diagnosis and treatment of endometriosis. Accordingly, in Specific Aim 1, we will refine positron emission tomography- computed tomography (PET-CT) with estrogen and progesterone receptor-specific tracers. We will monitor endometriotic lesion size and abundance in macaques by PET-CT and ultrasound and compare the results with a laparoscopic examination, which is currently the "gold standard" for staging the disease. In Specific Aim 2, we will evaluate cellular mediators of inflammation, progesterone resistance, and metabolic response in serum, peritoneal fluid, endometrium, and endometrial lesions; and quantify immune cell infiltration in endometriotic lesions from macaques. We will correlate these measures with the lesion burden detected by PET-CT and laparoscopy. In Specific Aim 3, we will use the macaque endometriosis model to test the effect of inhibitors against SIRT1 (Selisistat; EX-527) and the glycolytic enzyme, pyruvate dehydrogenase (dichloroacetate; DCA). During each aim, macaque samples will be archived for future study, and relevant findings will be used to inform Project 1 (Dr. Young, PI; involving PET/MRI imaging and inflammation of the disease in women) and Project 2 (Dr. Jeong, PI; involving the role of SIRT1 in mediating progesterone resistance). This work is highly complementary to the other proposed projects and will support our long-term goal of advancing novel therapies for this debilitating disease in women.