Complex inflammatory mechanisms and therapeutic targeting in endometriosis

项目总结/摘要 据估计，子宫内膜异位症影响10%的育龄妇女。它导致相当多的发病率， 慢性和使人衰弱的疼痛，严重影响妇女及其家庭的生活质量。因为 它是一种雌激素依赖性疾病，激素疗法可用于药物治疗， 子宫内膜异位症然而，这些激素治疗沿着腹腔镜手术往往是有限的 疗效高复发率、频繁的副作用、额外的成本和潜在的发病率。因此 迫切需要开发新的和有效的治疗子宫内膜异位症的靶向生物学上重要的 这种疾病的病理生理学机制。子宫内膜异位症是一种慢性炎症 疾病异常的炎性功能障碍有助于疾病的发展和进展。我们 最近确定了一种小分子，氯硝柳胺（Niclo），可以作为一种潜在的新的有效， 子宫内膜异位症的治疗方法有哪些？我们已经证明， 使用小鼠通过炎症信号传导减少类风湿病病变（ELL）的生长和进展 子宫内膜异位症模型。我们的研究表明，腹腔液中的大MΦ（LPM）增加 (PF)的ELL小鼠，并侵入ELL。PF中升高的LPM群体被Niclo降低。Niclo 还抑制PF、ELL、盆腔器官（子宫和阴道）和背部 ELL内MΦ浸润、血管化和神经支配。所以我们 假设了解与子宫内膜异位症相关的复杂慢性炎症机制 对于开发新的治疗策略至关重要，并为靶向免疫功能障碍提供了理论基础。 本申请的目的是通过检查来测试这一假设：1）LPM的损失如何影响 子宫内膜异位症的病理生理学，2）ELL诱导如何改变ELL的功能异质性群体 和腹膜渗出液细胞，以及它们的炎症功能障碍如何被Niclo抑制，以及3）如何抑制 Niclo的相互作用与疼痛相关的神经病学相关。Niclo是一种有效的食品和药物 管理局批准的药物，用于治疗蠕虫病的人，已使用了几十年。 因此，Niclo的药物再利用可能导致快速分布，生育保留和有效的非- 激素疗法比目前的疗法副作用更少。

PROJECT SUMMARY/ABSTRACT Endometriosis is estimated to affect 10% of reproductive age women. It results in considerable morbidity with chronic and debilitating pain, which substantially affect the quality of life of women and their families. Because it is an estrogen-dependent disorder, 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, frequent side effects, additional costs, and potential morbidity. Thus, a critical need exists to develop new and effective therapies for endometriosis targeting biologically important mechanisms that underlie pathophysiology of this disease. Endometriosis is known as a chronic inflammatory disease. Aberrant inflammatory dysfunction contributes to development and progression of the disease. We have recently determined a small molecule, niclosamide (Niclo) that could serve as a potential new effective, non-hormonal, fertility-sparing option for the treatment of endometriosis. We have demonstrated that Niclo reduces growth and progression of endometriosis-like lesions (ELL) via inflammatory signaling using a mouse model of endometriosis. Our studies show that large peritoneal MΦ (LPM) are increased in the peritoneal fluid (PF) of ELL mice and invaded into the ELL. Elevated LPM populations in the PF are reduced by Niclo. Niclo also inhibits aberrant inflammation established in the PF, ELL, pelvic organs (uterus and vagina) and dorsal root ganglion (DRG), as well as MΦ infiltration, vascularization and innervation in the ELL. Therefore, we hypothesize that understanding the complex chronic inflammatory mechanisms associated with endometriosis is crucial to develop a new therapeutic strategy and provides the rationale for targeting immune dysfunction. The objective of this application is to test this hypothesis by examining: 1) how loss of LPM impacts pathophysiology of endometriosis, 2) how ELL induction alters the functionally heterogenic population of ELL and peritoneal exudate cells, and how their inflammatory dysfunction is inhibited by Niclo and 3) how inhibitory interactions from Niclo correlate with pain-related symptomology. Niclo is an efficacious Food and Drug Administration-approved drug for the treatment of helminthosis in humans that has been used for decades. Thus, drug re-purposing of Niclo could result in a rapidly-distributable, fertility-sparing and effective non- hormonal therapy that has fewer side effects than current treatments.