Development of new therapeutic strategies for endometriosis

项目总结/摘要 子宫内膜异位症影响6-10%的育龄妇女，约50%的受影响妇女 经历严重的慢性盆腔疼痛和不孕症。因为子宫内膜异位症是一种雌激素依赖性 子宫内膜异位症的治疗方法有哪些？但这些 激素治疗沿着腹腔镜手术通常具有有限的疗效和高复发率。 此外，激素疗法具有许多不期望的副作用。因此，确定新的 治疗目标和有效的药物，以改善目前的治疗。众所周知，炎症 由于细胞因子、趋化因子、胰高血糖素和生长因子的过度产生， 子宫内膜异位症而子宫内膜、腹膜和子宫内膜中的促炎环境 病变涉及改变炎症和免疫反应、血管生成和 细胞凋亡，STAT 3信号转导已被报道为炎症和细胞存活的主要调节因子之一 子宫内膜异位症的病理生理学我们最近发现了一种小分子，氯硝柳胺， 是一种新的有效的，生育保留治疗子宫内膜异位症。我们证明氯硝柳胺减少了 使用子宫内膜异位症小鼠模型观察子宫内膜样病变的生长和进展。柳胺 抑制类增生病变和增生细胞系12 Z中的STAT 3活性。此外，委员会认为， 氯硝柳胺不破坏卵巢和子宫功能，包括发情周期、排卵、妊娠率， 胎龄和窝仔数。因此，我们的中心假设是氯硝柳胺降低了 炎症微环境和抑制巨噬细胞依赖性神经血管生成，这是一个标志， 子宫内膜异位症通过抑制STAT 3信号传导。目的是检查是否靶向STAT 3 氯硝柳胺在雌激素和免疫细胞（巨噬细胞）中的信号传导足以抑制雌激素， 驱动炎症微环境。我们还将评估氯硝柳胺是否能有效减少 巨噬细胞浸润与异常的神经血管生成有关，这是一个重要的发病机制， 增生性病变。氯硝柳胺是一种有效的和最低毒性，食品和药物管理局- 已批准用于治疗人类蠕虫病的药物，并已用于患者， 几十年因此，氯硝柳胺的药物再利用可能导致快速分配，廉价，生育- 保守而有效的治疗方法对于治疗子宫内膜异位症的患者会有少得多的副作用 比目前的治疗效果。

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.