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/摘要子宫内膜异位症是生殖年龄妇女的炎症妇科疾病。两个主要症状是慢性骨盆疼痛和不育，对生殖健康和生活质量产生深远的影响。专业人士子宫内膜病变，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，导致慢性骨盆疼痛和不育。新兴证据表明子宫内膜异位症中的骨盆疼痛是内脏炎症和神经性疼痛的结合。长期目标是了解子宫内膜异位症的分子和细胞发病机理，并鉴定非甾体类药物用于子宫内膜异位症的治疗。古老的药用植物Withania Somnifera已被用来治疗炎症疾病，神经系统疾病/疾病，神经性和炎症性疼痛以及癌症。广泛的 Withania somnifera的治疗作用通过其活性类固醇内酯与AFERIN-A施加。然而，尚无研究研究Withania somnifera/withaferin-a在子宫内膜异位中的作用。提议的及时所需的假设驱动的新型临床前研究的重点是withaferin-a的治疗作用子宫内膜异位症。总体假设：用大蛋白A的治疗抑制了生长和存活子宫内膜损伤，改善骨盆疼痛，并恢复子宫内膜微环境以支持生育能力。目的：确定伴有AFERIN-A对子宫内膜生长的生长和存活的治疗作用病变，（ii）腹膜腔，子宫内膜病变和疼痛脑部的促炎状态，（iii）促疾病子宫内膜的炎症和激素微环境（IV）上皮和基质细胞特异性基因子宫内膜病变和子宫内膜的签名，（v）上升和下降疼痛途径，中央敏化以及潜在的分子和细胞机制，以及（vi）骨盆疼痛阈值和自发疼痛。特定的AIM-1将确定伴有AFERIN-A对子宫内膜病变的治疗作用和子宫内膜。特定的AIM-2将确定Aferin-A对中心疼痛的治疗作用子宫内膜异位中的机制。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，脑神经元的电生理学，上升和下降疼痛，疼痛行为，体内生物成像，荧光显微镜和流式细胞仪。创新和影响：新的获得的信息应填补有关（i）中心中用AFERIN-A的治疗作用的知识的空白骨盆疼痛的机制，疼痛区域中的基因表达特征以及它们与慢性的关联子宫内膜异位症的骨盆疼痛；（ii）上皮和基质细胞特异性基因表达签名子宫内膜损伤及其与子宫内膜病变的生长和生存的关联；（iii）上皮子宫内膜中的基因细胞特异性基因表达特征及其与不育症的关联。（iv）新颖的结果将建立分子治疗和临床前的基础，以将Aferin-A用作非 - 子宫内膜异位症女性治疗骨盆疼痛和不育症的类固醇和非阿片类药物疗法。