PROJECT SUMMARY/ABSTRACT Endometriosis affects 6-10% of women of reproductive age, and approximately 50% of affected women experience severe chronic pelvic pain and infertility. Because endometriosis is an estrogen-dependent disease, hormonal therapies are available for the medical treatment of endometriosis. However, these hormonal treatments along with laparoscopic surgery are often of limited efficacy with high recurrence rates. Furthermore, hormone therapy has many undesired side effects. Therefore, it is important to identify new therapeutic targets and efficient drugs that improve current treatment. It has been well-known that inflammation as a result of the over production of cytokines, chemokines, prostaglandins and growth factors is a feature of endometriosis. While the proinflammatory environment in the endometrium, peritoneum and endometriotic lesions involves complex mechanisms altering inflammatory and immune responses, angiogenesis and apoptosis, STAT3 signaling has been reported as one of the main regulators of inflammation and cell survival in the pathophysiology of endometriosis. We have recently identified a small molecule, niclosamide that could be a new effective, fertility-sparing therapy for endometriosis. We demonstrated that niclosamide reduced growth and progression of endometriosis-like lesions using a mouse model of endometriosis. Niclosamide inhibited STAT3 activity in endometriosis-like lesions and the endometriotic cell line, 12Z. Furthermore, niclosamide did not disrupt ovarian and uterine functions including estrous cycles, ovulation, pregnancy rates, gestational length and litter size. Therefore, our central hypothesis is that niclosamide reduces the inflammatory microenvironment and inhibits macrophage-dependent neuroangiogenesis that is a hallmark of endometriosis through inhibition of STAT3 signaling. The objective is to examine whether targeting STAT3 signaling by niclosamide in endometriotic and immune cells (macrophages) is sufficient to inhibit the estrogen- driven inflammatory microenvironment. We will also assess whether niclosamide is effective to reduce macrophage infiltration which is associated with abnormal neuroangiogenesis, a critical pathogenesis of endometriotic lesions. Niclosamide is an efficacious and minimally toxic, Food and Drug Administration- approved drug for the treatment of helminthosis in humans, and has been used in patients for this purpose for decades. Thus, drug re-purposing of niclosamide could result in a rapidly-distributable, inexpensive, fertility- sparing and effective therapy for the treatment of endometriosis patients that would have much fewer side effects than current treatments.