Development of new therapeutic strategies for endometriosis

子宫内膜异位症新治疗策略的开发

基本信息

批准号：
9373498
负责人：
KANAKO HAYASHI
金额：
$ 18.44万
依托单位：
SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9373498
关键词：
Adhesions Adverse effects Affect Age Agonist Apoptosis Cell Line Cell Survival Cells Complex Development Disease Dysmenorrhea Dyspareunia Endometrium Environment Estrogen Receptors Estrogens Estrous Cycle Exhibits Female Genital Diseases Female infertility Fertility Functional disorder GNRH1 gene Goals Growth Growth Factor Health Hormonal Human Immune Immune response Infertility Infiltration Inflammation Inflammatory Inflammatory Response Laparoscopic Surgical Procedures Length Lesion Litter Size Medical Morbidity - disease rate Nerve Fibers Oral Contraceptives Ovarian Ovulation Pathogenesis Patient-Focused Outcomes Patients Peritoneal Peritoneum Pharmaceutical Preparations Pharmacotherapy Phenotype Pregnancy Pregnancy Rate Production Progestins Prostaglandins Recurrence Reporting Research STAT3 gene Signal Transduction Stromal Cells Therapeutic United States Food and Drug Administration Uterine hemorrhage Vascularization Woman angiogenesis chemokine chronic pelvic pain cost cytokine effective therapy endometriosis experience hormone therapy improved macrophage mouse model new therapeutic target novel novel therapeutic intervention receptor expression reproductive small molecule

项目摘要

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.

项目概要/摘要子宫内膜异位症影响 6-10% 的育龄女性，约 50% 受影响的女性经历严重的慢性盆腔疼痛和不孕。因为子宫内膜异位症是一种雌激素依赖性病疾病，激素疗法可用于子宫内膜异位症的医学治疗。然而，这些激素治疗和腹腔镜手术通常疗效有限且复发率高。此外，激素疗法有许多不良副作用。因此，识别新的治疗靶点和改善当前治疗的有效药物。众所周知，炎症由于细胞因子、趋化因子、前列腺素和生长因子的过度产生，这是子宫内膜异位症。而子宫内膜、腹膜和子宫内膜异位症的促炎环境病变涉及改变炎症和免疫反应、血管生成和据报道，STAT3 信号传导是炎症和细胞存活的主要调节因子之一在子宫内膜异位症的病理生理学中。我们最近发现了一种小分子氯硝柳胺，它可以成为治疗子宫内膜异位症的一种新的有效的、保留生育能力的疗法。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异位症样病变的生长和进展。氯硝柳胺抑制子宫内膜异位症样病变和子宫内膜异位细胞系 12Z 中的 STAT3 活性。此外，氯硝柳胺不会破坏卵巢和子宫功能，包括动情周期、排卵、妊娠率、妊娠长度和窝产数。因此，我们的中心假设是氯硝柳胺可降低炎症微环境并抑制巨噬细胞依赖性神经血管生成，这是通过抑制 STAT3 信号传导来治疗子宫内膜异位症。目的是检查是否靶向 STAT3 子宫内膜异位细胞和免疫细胞（巨噬细胞）中氯硝柳胺的信号传导足以抑制雌激素驱动的炎症微环境。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神经血管生成有关，这是神经血管生成的关键发病机制子宫内膜异位病变。氯硝柳胺是一种有效且毒性最小的药物，美国食品和药物管理局- 批准用于治疗人类蠕虫病的药物，并已用于患者用于此目的几十年。因此，氯硝柳胺的药物再利用可能会导致一种可快速分配、廉价、生育力强的药物。用于治疗子宫内膜异位症患者的节省且有效的疗法，其副作用会少得多效果优于现有治疗方法。