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: 10376245
• 负责人: KANAKO HAYASHI
• 金额: $ 46.43万
• 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/10376245
• 关键词: Adhesives; Affect; Age; Agonist; Ascites; 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 pain; chronic pelvic pain; conditional knockout; cost; debilitating pain; 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.

项目摘要/摘要 子宫内膜异位症估计会影响10％的生殖年龄妇女。它导致相当大的发病率 慢性和使人衰弱的疼痛极大地影响了妇女及其家人的生活质量。因为 这是一种雌激素依赖性疾病，可用于荷尔蒙疗法可用于 子宫内膜异位症。但是，这些骑马以及腹腔镜手术通常有限 具有高复发率，经常副作用，额外成本和潜在发病率的影响。那， 存在批判性需求，以开发针对生物学重要的子宫内膜异位症的新有效疗法 该疾病的病理生理基础的机制。子宫内膜异位症被称为慢性炎症 疾病。异常炎症功能障碍有助于疾病的发展和发展。我们 最近已经确定了一个小分子烟酰胺（Niclo），可以作为潜在的新有效， 用于子宫内膜异位症治疗的非激素，保留生育能力的选择。我们已经证明了Niclo 使用小鼠通过炎症信号传导来减少子宫内膜异位症状病变（ELL）的生长和进展 我们的研究表明，腹膜液中大腹膜Mφ（LPM）增加 （PF）ELL小鼠并入侵ELL。 NICLO降低了PF中的LPM升高。 还抑制在PF，ELL，骨盆器官（子宫和阴道）和背侧建立的异常炎症 根神经节（DRG）以及ELL中的Mφ浸润，血管化和神经。因此，我们 假设了解与子宫内膜异位有关的复杂慢性炎症机制 对于制定新的理论策略至关重要，并为靶向免疫功能障碍提供了理由。 该应用的目的是通过检查以下方法检验以下方法：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功能异性群 和腹膜渗出细胞，以及如何抑制Niclo和3）如何抑制其炎症功能障碍 Niclo的相互作用与疼痛相关的症状相关。尼洛是一种有效的食物和药物 几十年来，已批准的药物用于治疗人类的胚芽病。 这是尼古拉的药物重复使用可能会导致迅速分布，具有生育能力和有效的非 - 副作用比目前治疗少的激素疗法。