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

焦点：局限性外阴疼痛(LPV)是慢性性交困难(疼痛)的最常见原因 在绝经前的妇女中)，而且它仍然是一种鲜为人知的疾病。现有的治疗方法不能 瞄准根本原因，治疗是反复尝试，干预通常会升级为切断 阴道口、前庭周围的疼痛组织。该提案旨在确定新的目标，以 治疗LPV疼痛与至少两个NIH研究所的使命一致，旨在1)改善女性的 医疗保健(NICHD)和2)确定疼痛治疗的非成瘾目标(NIDA)。 前提：我们在LPV患者的前庭发现了一种非经典的炎症反应，即 导致LPV疼痛的关键因素。LPV患者的前庭对炎症刺激高度敏感，导致 以高水平的促炎为特征的不会发生的反应 调解人。促炎介质水平和疼痛之间有直接联系；成纤维细胞 从极度疼痛的部位产生最高水平的这些介质，表明前庭可能是 独一无二的脆弱，可以专门针对解决疼痛。我们随后确定了几个 治疗干预的候选对象(例如Dectin-1、核Kappa因子B)。然而，以这些为目标将 不能完全缓解促炎信号或可能损害宿主防御。我们的目标是找出 并验证LPV疼痛治疗的新治疗靶点。我们的支持数据有力地表明，瞬变 受体潜在的香草酸受体4(TRPV4)及其信号通路成员代表着很有前途的 创新的治疗靶点。我们将确认TRPV4的S在LPV中的作用，验证可能的治疗靶点，并 在这个过程中，提高我们对外阴疼痛的机械性认识。 组织假说：我们假设靶向TRPV4通路将减少前伤害感受 人成纤维细胞和组织中的信号与小鼠的镇痛作用 具体目标1：阐明位点特异性TRPV4信号差异在确定新的治疗方法中的作用 LPV的目标。 特定目标2：探讨炎症、TRPV4和LPV的脂代谢改变之间的关系 病人。 具体目标3：使用3D组织培养和活体LPV模型验证TRPV4和其他已识别的靶点。 对现场的影响：我们计划实现三个目标：1)确定和验证绝望的新目标 需要非侵入性有效的外阴疼痛治疗，2)提高对外阴疼痛的认识 机制，以及3)通过关注无处不在的 被怀疑在疼痛综合征中发挥作用的信号通路(TRPV4)，其靶向不太可能 导致不良后遗症，包括药物依赖障碍。

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.