Transient Vanilloid Receptors and Vulvar Pain: New Therapeutic Targets for Vulvodynia

瞬时香草酸受体和外阴疼痛：外阴痛的新治疗靶点

• 批准号: 10582414
• 负责人: Megan Lindsay Falsetta Wood
• 金额: $ 61.94万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582414
• 关键词: 3-Dimensional; Absence of pain sensation; Age; Agonist; Analgesics; Area; Biological Assay; Biopsy; Cell Fractionation; Cells; Chronic; Clinical; Complement Factor B; Data; Dependence; Dinoprostone; Disease; Drug Addiction; Dyspareunia; Enzyme-Linked Immunosorbent Assay; Evaluation; Family; Fibroblasts; Genetic Transcription; Goals; Healthcare; Host Defense; Human; Hyperalgesia; Hyperthermia; Immune; Immunohistochemistry; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-6; Intervention; Libraries; Light; Link; Lipids; Luciferases; Mass Spectrum Analysis; Measures; Mediating; Mediator; Methods; Mission; Modeling; Mus; National Institute of Child Health and Human Development; National Institute of Drug Abuse; Nociception; Nuclear; Operative Surgical Procedures; Opiate Addiction; PAR-2 Receptor; Pain; Pain Threshold; Pain management; Painless; Pathway interactions; Patients; Perception; Persistent pain; Pharmaceutical Preparations; Play; Premenopause; Process; Production; Quality of life; Quantitative Reverse Transcriptase PCR; Reporter; Reproducibility; Risk; Role; Sensory; Serotonin; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Stimulus; Syndrome; Tampons; Techniques; Temperature; Therapeutic Intervention; Tissues; Topical application; Touch sensation; United States National Institutes of Health; Vagina; Vestibule; Vulva; Vulvodynia; Walking; Western Blotting; Woman; Women' s Health; allodynia; antagonist; capsaicin receptor; chronic painful condition; cytokine; dectin 1; design; drug development; human tissue; improved; in vivo; innovation; member; new therapeutic target; novel therapeutics; opioid epidemic; pain symptom; prevent; receptor; release of sequestered calcium ion into cytoplasm; reproductive; response; sexual relationship; targeted treatment; therapeutic candidate; therapeutic development; therapeutic target; therapeutically effective; tissue culture; vulvar pain

The Focus: Localized provoked vulvodynia (LPV) is the most common cause of chronic dyspareunia (painful intercourse) in premenopausal women, and it remains a poorly understood disease. Existing therapies do not target the underlying causes, treatment is trial and error, and intervention typically escalates to cutting away the painful tissue surrounding the vaginal opening, the vestibule. This proposal aims to identify new targets to treat LPV pain in alignment with the missions of at least two NIH institutes by aiming to 1) improve women’s health care (NICHD) and 2) identify non-addictive targets for pain therapy (NIDA). The Premise: We discovered a non-classical inflammatory response in the vestibule of LPV patients that is a key contributor to LPV pain. The vestibule of LPV patients is hypersensitive to inflammatory stimuli, causing a response when one would not otherwise occur, which is characterized by high levels of proinflammatory mediators. There is a direct association between proinflammatory mediator levels and pain; fibroblasts taken from sites of exquisite pain produce the highest levels of these mediators, indicating the vestibule could be uniquely vulnerable and could be specifically targeted to resolve pain. We subsequently identified several candidates for therapeutic intervention (e.g. Dectin-1, Nuclear kappa factor B). However, targeting these would not completely alleviate proinflammatory signaling or might compromise host defenses. Our goal is to identify and validate new therapeutic targets for LPV pain therapy. Our supporting data strongly suggest that transient receptor potential vanilloid receptor 4 (TRPV4) and members of its signaling pathway represent promising and innovative therapeutic targets. We will confirm TRPV4’s role in LPV, validate the likely therapeutic targets, and in the process, enhance our mechanistic understanding of vulvodynia. Organizing Hypothesis: We hypothesize that targeting the TRPV4 pathway will reduce pro-nociceptive signaling in human fibroblasts and tissue and impart analgesia in mice Specific Aim 1: Elucidate the role of site-specific TRPV4 signaling differences to identify new therapeutic targets for LPV. Specific Aim 2: Explore the relationship between inflammation, TRPV4, and alterations in lipid profiles in LPV patients. Specific Aim 3: Validate TRPV4 and other identified targets using 3D tissue culture and an in vivo LPV model. Impact on the field: We plan to accomplish three goals: 1) identify and validate new targets for desperately needed non-invasive and efficacious vulvodynia therapies, 2) improve understanding of the vulvodynia mechanism, and 3) identify mechanisms likely conserved in other pain conditions by focusing on a ubiquitous signaling pathway (TRPV4) suspected to play a role in pain syndromes, targeting of which would be unlikely to result in adverse sequelae, including drug dependence disorders.

焦点：局部诱发性外阴痛 (LPV) 是慢性性交痛（疼痛）的最常见原因。 性交）在绝经前女性中，它仍然是一种人们知之甚少的疾病，现有的治疗方法无法解决这一问题。 针对根本原因，治疗是反复试验，干预通常升级为切除 该提案旨在确定阴道口周围的疼痛组织，即前庭。 治疗 LPV 疼痛符合至少两个 NIH 机构的使命，目标是 1) 改善女性的疼痛 医疗保健 (NICHD) 和 2) 确定疼痛治疗的非成瘾目标 (NIDA)。 前提：我们发现 LPV 患者前庭存在非典型炎症反应，这是一种 LPV 患者的前庭对炎症刺激高度敏感，从而导致 LPV 疼痛。 当一种情况不会发生时的反应，其特征是高水平的促炎物质 促炎介质水平与成纤维细胞的摄入量有直接关系； 从剧烈疼痛的部位产生最高水平的这些介质，表明前庭可能是 我们随后确定了一些独特的脆弱性，并且可以专门针对解决疼痛。 治疗干预的候选者（例如 Dectin-1、核 kappa 因子 B）。 不能完全缓解促炎症信号传导或可能损害宿主防御。 并验证 LPV 疼痛治疗的新治疗靶点。我们的支持数据强烈表明短暂性。 受体潜力 香草酸受体 4 (TRPV4) 及其信号通路成员代表着有前途和 我们将确认 TRPV4 在 LPV 中的作用，验证可能的治疗靶点，以及 在此过程中，增强我们对外阴痛的机械理解。 组织假设：我们发现，针对 TRPV4 途径将减少促伤害感受 人类成纤维细胞和组织中的信号传导并赋予小鼠镇痛作用 具体目标 1：阐明位点特异性 TRPV4 信号差异的作用，以确定新的治疗方法 LPV 的目标。 具体目标 2：探索炎症、TRPV4 和 LPV 脂质谱变化之间的关系 患者。 具体目标 3：使用 3D 组织培养和体内 LPV 模型验证 TRPV4 和其他已识别的靶标。 对领域的影响：我们计划实现三个目标：1）确定并验证迫切需要的新目标 需要非侵入性和有效的外阴痛治疗，2）提高对外阴痛的认识 机制，3）通过关注普遍存在的机制来确定其他疼痛条件下可能保守的机制 信号通路（TRPV4）被怀疑在疼痛综合征中发挥作用，但不太可能针对该信号通路 导致不良后遗症，包括药物依赖障碍。