Complex inflammatory mechanisms and therapeutic targeting in endometriosis

项目摘要/摘要 据估计，10%的育龄妇女患有子宫内膜异位症。它会导致相当大的发病率 慢性和衰弱的疼痛，对妇女及其家庭的生活质量有很大影响。因为 它是一种雌激素依赖型疾病，激素疗法可用于治疗 子宫内膜异位症。然而，这些激素治疗和腹腔镜手术往往是有限的。 高复发率、频繁的副作用、额外的费用和潜在的发病率。因此，一个 迫切需要开发针对生物学重要性的治疗子宫内膜异位症的新的有效疗法 这种疾病的病理生理学基础的机制。子宫内膜异位症是一种慢性炎症性疾病 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)，可能是一种潜在的新有效药物， 用于治疗子宫内膜异位症的非激素、节育选择。我们已经证明了尼克洛 使用小鼠通过炎症信号减少子宫内膜异位症样病变(ELL)的生长和进展 子宫内膜异位症模型。我们的研究表明，腹腔液中的大腹膜MΦ(LPM)增加 (PF)，并侵入ELL。在PF中，升高的LPM种群被Niclo减少。尼克洛 还可抑制在盆腔器官(子宫和阴道)和背部形成的异常炎症。 根神经节和M-Φ在ELL内的渗透、血管化和神经支配。因此，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 对于开发一种新的治疗策略至关重要，并为针对免疫功能障碍提供了理论基础。 此应用程序的目标是通过检查以下各项来检验这一假设：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 和腹膜渗出细胞，以及NICLO如何抑制它们的炎症功能障碍，以及3)如何抑制 来自Niclo的互动与疼痛相关的症状相关。尼克罗是一种有效的食品和药物 美国政府批准的治疗人体蠕虫病的药物，已使用数十年。 因此，NICLO的药物再利用可能导致快速分配、节省生育能力和有效的非 比目前的治疗方法副作用更少的激素疗法。

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.