Phytotherapy for Endometriosis

子宫内膜异位症的植物疗法

• 批准号: 10530788
• 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
• 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/10530788
• 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; Opioid; Pain; Pain Threshold; Pain management; Pathogenesis; Pathologic; Pathway interactions; Patients; Pelvic Pain; Phytotherapy; Prevalence; Proteins; Quality of life; RNA analysis; Reproductive Health; Research; Role; Steroids; 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

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.

抽象/总结