Phytotherapy for Endometriosis

子宫内膜异位症的植物疗法

基本信息

批准号：
10693398
负责人：
Joe A. Arosh
金额：
$ 32.57万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693398
关键词：
Affect Age Allografting Animals Area Ashwagandha Brain Brain region Cell Survival Cells Clinical Disease Electrophysiology (science)Endometrial Endometrium Epithelial Cells Female Genital Diseases Female infertility Fertility Flow Cytometry Fluorescence Microscopy Gene Expression Gene Expression Profile Goals Greater sac of peritoneum Growth Hormonal Immune Infertility Inflammatory Intervention Knowledge Lactones Lesion Malignant Neoplasms Measures Medicinal Plants Molecular Neurons Nucleotides Pain Pain Threshold Pain management Pathogenesis Pathologic Pathway interactions Patients Pelvic Pain Phytotherapy Prevalence Proteins Quality of life Reproductive Health Research Role Stromal Cells Synaptic Transmission Thalamic structure Therapeutic Therapeutic Effect Time Uterine cavity Visceral Woman behavior measurement behavioral study bioimaging cell growth central pain central sensitization chemokine chronic pain chronic pelvic pain cytokine endometriosis genetic signature immunocytochemistry in vivo inflammatory pain innovation laser capture microdissection midbrain central gray substance mouse model nervous system disorder neuroinflammation non-opioid analgesic novel osmotic minipump pain behavior pain model pain perception pain relief painful neuropathy peripheral pain persistent symptom pre-clinical pre-clinical research protein expression reproductive reproductive system disorder spontaneous pain subcutaneous transcriptome sequencing

项目摘要

ABSTRACT/SUMMARY Endometriosis is an inflammatory gynecological disease of reproductive-age women. The two major symptoms are chronic pelvic pain and infertility, which profoundly affect reproductive health and life quality. The pro- inflammatory microenvironment of the endometriotic lesions, endometrium, and the peritoneal cavity are the hallmarks of endometriosis, which leads to chronic pelvic pain and infertility. Emerging evidence suggests that pelvic pain in endometriosis is a combination of visceral inflammatory and neuropathic pain. The long-term goals are to understand the molecular and cellular pathogenesis of endometriosis and identify non-steroidal therapy for endometriosis. Withania somnifera, an ancient medicinal plant, has been used to treat inflammatory disorders, neurological diseases/disorders, neuropathic and inflammatory pain, and cancers. A wide range of therapeutic effects of Withania somnifera is exerted through its active steroidal lactone Withaferin-A. However, no studies have investigated the role of Withania somnifera/Withaferin-A in endometriosis. The proposed timely needed hypothesis-driven novel preclinical research is focused on the therapeutic effects of Withaferin-A in endometriosis. Overarching Hypothesis: Treatment of Withaferin-A suppresses the growth and survival of endometriotic lesions, ameliorates pelvic pain, and restores the endometrial microenvironment to support fertility. Objectives: Determine the therapeutic effects of Withaferin-A on (i) growth and survival of the endometriotic lesions, (ii) pro-inflammatory state of the peritoneal cavity, endometriotic lesions, and pain-brain areas, (iii) pro- inflammatory and hormonal microenvironment of the endometrium, (iv) epithelial and stromal cell-specific gene signatures in the endometriotic lesions and endometrium, (v) ascending and descending pain pathway and central sensitization and the underlying molecular and cellular mechanisms, and (vi) pelvic pain threshold and spontaneous pain. Specific Aim-1 will determine the therapeutic effects of Withaferin-A on endometriotic lesions and endometrium. Specific Aim-2 will determine the therapeutic effects of Withaferin-A on central pain mechanisms in endometriosis. The experimental approaches include the preclinical allograft mouse model of endometriosis, RNA-Seq, electrophysiology of brain neurons, ascending and descending pain pathways, pain behavior, in vivo bioimaging, fluorescence microscopy, and flow cytometry. Innovation and Impact: The new information obtained should fill the gap in the knowledge on therapeutic effects of Withaferin-A in (i) central mechanisms of pelvic pain, gene expression signatures in the pain-brain areas, and their association with chronic pelvic pain in endometriosis; (ii) epithelial and stromal cell-specific gene expression signatures in the endometriotic lesions and their association with growth and survival of endometriotic lesions; and (iii) epithelial and stromal cell-specific gene expression signatures in the endometrium and their association with infertility. (iv) The novel results will establish a molecular therapeutic and preclinical basis to use Withaferin-A as a non- steroidal and non-opioid therapy to treat pelvic pain and infertility in women with endometriosis.

摘要/总结子宫内膜异位症是育龄妇女的一种炎症性妇科疾病。两大症状慢性盆腔疼痛和不孕症，深刻影响生殖健康和生活质量。亲子宫内膜异位病灶、子宫内膜和腹膜腔的炎症微环境是子宫内膜异位症的标志，导致慢性盆腔疼痛和不孕。新出现的证据表明子宫内膜异位症的盆腔疼痛是内脏炎症和神经性疼痛的结合。长期来看目标是了解子宫内膜异位症的分子和细胞发病机制并识别非甾体类药物子宫内膜异位症的治疗。 Withania somnifera 是一种古老的药用植物，已被用于治疗炎症疾病、神经系统疾病/紊乱、神经性疼痛和炎性疼痛以及癌症。范围广泛睡茄的治疗作用是通过其活性甾体内酯 Withaferin-A 发挥的。然而，尚无研究调查睡茄/睡茄素 A 在子宫内膜异位症中的作用。建议及时所需的假设驱动的新型临床前研究重点是 Withaferin-A 在以下疾病中的治疗效果：子宫内膜异位症。总体假设：Withaferin-A 的治疗可抑制细胞的生长和存活子宫内膜异位病变，减轻盆腔疼痛，恢复子宫内膜微环境以支持生育能力。目的：确定睡茄素 A 对 (i) 子宫内膜异位症生长和存活的治疗效果病变，(ii) 腹膜腔、子宫内膜异位病变和痛脑区域的促炎症状态，(iii) 子宫内膜的炎症和激素微环境，(iv) 上皮细胞和基质细胞特异性基因子宫内膜异位病变和子宫内膜的特征，(v) 上升和下降疼痛通路和中枢敏化和潜在的分子和细胞机制，以及（vi）盆腔疼痛阈值和自发性疼痛。具体的Aim-1将决定Withaferin-A对子宫内膜异位病变的治疗效果和子宫内膜。具体的 Aim-2 将确定 Withaferin-A 对中枢性疼痛的治疗效果子宫内膜异位症的机制。实验方法包括临床前同种异体移植小鼠模型子宫内膜异位症、RNA-Seq、脑神经元电生理学、上升和下降疼痛通路、疼痛行为、体内生物成像、荧光显微镜和流式细胞术。创新和影响：新的所获得的信息应填补关于睡茄素 A 在 (i) 中枢神经系统中的治疗作用的知识空白。盆腔疼痛的机制、痛脑区域的基因表达特征及其与慢性疼痛的关系子宫内膜异位症引起的盆腔疼痛； (ii) 上皮细胞和基质细胞特异性基因表达特征子宫内膜异位病变及其与子宫内膜异位病变生长和存活的关系； (iii) 上皮细胞子宫内膜中基质细胞特异性基因表达特征及其与不孕症的关联。（四）新的结果将为使用 Withaferin-A 作为非药物奠定分子治疗和临床前基础。类固醇和非阿片类药物治疗子宫内膜异位症女性的盆腔疼痛和不孕症。