Complex inflammatory mechanisms and therapeutic targeting in endometriosis

子宫内膜异位症的复杂炎症机制和治疗靶向

• 批准号: 10178341
• 负责人: KANAKO HAYASHI
• 金额: $ 41.51万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10178341
• 关键词: Adhesives; Affect; Age; Agonist; Ascites; Biological; Cells; Chronic; Complex; Data; Development; Disease; Disease Progression; Environment; Estrogens; Estrous Cycle; FDA approved; Family; Fertility; Functional disorder; GNRH1 gene; Ganglia; Growth; Health; Hormonal; Human; Hyperalgesia; Immune System Diseases; Immune Targeting; Infiltration; Inflammation; Inflammatory; Innovative Therapy; Invaded; Knockout Mice; Laparoscopic Surgical Procedures; Length; Lesion; Medical; Morbidity - disease rate; Mus; Oral Contraceptives; Organ; Ovarian; Ovulation; Pain; Patient-Focused Outcomes; Pelvic cavity structure; Pelvis; Peritoneal; Peritoneal Fluid; Pharmaceutical Preparations; Pharmacotherapy; Plant Roots; Population; Pregnancy; Pregnancy Rate; Production; Progestins; Publishing; Quality of life; Recurrence; Research; Role; Signal Transduction; Source; Spinal Ganglia; Testing; United States Food and Drug Administration; Uterus; Vagina; Vascularization; Woman; associated symptom; behavior test; chronic inflammatory disease; chronic pelvic pain; conditional knockout; cost; effective therapy; endometriosis; eutopic endometrium; hormone therapy; improved; macrophage; mouse model; nerve supply; new therapeutic target; novel therapeutic intervention; novel therapeutics; reproductive; side effect; single-cell RNA sequencing; small molecule; subfertility; therapeutic target

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.

项目概要/摘要 据估计，子宫内膜异位症影响着 10% 的育龄妇女。它导致相当大的发病率 慢性和使人衰弱的疼痛，严重影响妇女及其家人的生活质量。因为 它是一种雌激素依赖性疾病，激素疗法可用于治疗 子宫内膜异位症。然而，这些激素治疗以及腹腔镜手术的效果往往有限。 疗效高，复发率高，副作用频繁，额外费用和潜在的发病率。因此，一个 迫切需要针对具有重要生物学意义的子宫内膜异位症开发新的有效疗法 该疾病的病理生理学机制。子宫内膜异位症被称为慢性炎症 疾病。异常的炎症功能障碍有助于疾病的发生和进展。我们 最近确定了一种小分子，氯硝柳胺（Niclo），它可以作为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、保留生育能力的选择。我们已经证明了尼科洛 使用小鼠通过炎症信号传导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，腹膜液中的大腹膜 MΦ (LPM) 增加 (PF) 的 ELL 小鼠并侵入 ELL。 Niclo 可减少 PF 中升高的 LPM 数量。尼科洛 还抑制 PF、ELL、盆腔器官（子宫和阴道）和背侧的异常炎症 根神经节 (DRG)，以及 ELL 中的 MΦ 浸润、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。 此应用程序的目的是通过检查以下内容来检验该假设：1) LPM 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 的功能异质群体 和腹膜渗出细胞，以及 Niclo 如何抑制其炎症功能障碍，以及 3) 如何抑制 Niclo 的相互作用与疼痛相关症状相关。尼克劳是一种有效的食品和药物 经政府批准用于治疗人类蠕虫病的药物，已使用数十年。 因此，尼氯洛的药物重新利用可能会产生一种可快速分配、保留生育能力且有效的非 荷尔蒙疗法比目前的疗法副作用更少。