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
基本信息
- 批准号:10582414
- 负责人:
- 金额:$ 61.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:3-DimensionalAbsence of pain sensationAgeAgonistAnalgesicsAreaBiological AssayBiopsyCell FractionationCellsChronicClinicalComplement Factor BDataDependenceDinoprostoneDiseaseDrug AddictionDyspareuniaEnzyme-Linked Immunosorbent AssayEvaluationFamilyFibroblastsGenetic TranscriptionGoalsHealthcareHost DefenseHumanHyperalgesiaHyperthermiaImmuneImmunohistochemistryImpairmentInflammationInflammation MediatorsInflammatoryInflammatory ResponseInterleukin-6InterventionLibrariesLightLinkLipidsLuciferasesMass Spectrum AnalysisMeasuresMediatingMediatorMethodsMissionModelingMusNational Institute of Child Health and Human DevelopmentNational Institute of Drug AbuseNociceptionNuclearOperative Surgical ProceduresOpiate AddictionPAR-2 ReceptorPainPain ThresholdPain managementPainlessPathway interactionsPatientsPerceptionPersistent painPharmaceutical PreparationsPlayPremenopauseProcessProductionQuality of lifeQuantitative Reverse Transcriptase PCRReporterReproducibilityRiskRoleSensorySerotoninSignal PathwaySignal TransductionSiteSmall Interfering RNAStimulusSyndromeTamponsTechniquesTemperatureTherapeutic InterventionTissuesTopical applicationTouch sensationUnited States National Institutes of HealthVaginaVestibuleVulvaVulvodyniaWalkingWestern BlottingWomanWomen&aposs Healthallodyniaantagonistcapsaicin receptorchronic painful conditioncytokinedectin 1designdrug developmenthuman tissueimprovedin vivoinnovationmembernew therapeutic targetnovel therapeuticsopioid epidemicpain symptompreventreceptorrelease of sequestered calcium ion into cytoplasmreproductiveresponsesexual relationshiptargeted treatmenttherapeutic candidatetherapeutic developmenttherapeutic targettherapeutically effectivetissue culturevulvar pain
项目摘要
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:局部激发性外阴痛(LPV)是慢性性交困难(疼痛)的最常见原因
在绝经前妇女中,它仍然是一种知之甚少的疾病。现有的治疗方法不
针对根本原因,治疗是试验和错误,干预通常升级为切断
阴道口前庭周围的疼痛组织这项建议旨在确定新的目标,
治疗LPV疼痛与至少两个NIH研究所的任务一致,旨在1)改善妇女的
健康护理(NICHD)和2)确定疼痛治疗的非成瘾性靶点(NIDA)。
结论:我们在LPV患者前庭发现了一种非经典的炎症反应,
LPV疼痛的关键因素。LPV患者的前庭对炎症刺激过敏,导致
当一个反应不会发生时,其特征在于高水平的促炎性反应。
调解员促炎介质水平和疼痛之间存在直接联系;
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
特别脆弱,可以专门针对解决疼痛。我们随后确定了几个
用于治疗性干预的候选物(例如Dectin-1、核κ因子B)。然而,针对这些目标,
不能完全缓解促炎信号或可能损害宿主防御。我们的目标是确定
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,
受体电位香草素受体4(TRPV 4)及其信号通路成员代表了有前途的和
创新的治疗目标。我们将证实TRPV 4在LPV中的作用,验证可能的治疗靶点,
在这个过程中,提高我们对外阴痛的机械理解。
组织假说:我们假设靶向TRPV 4通路将减少促伤害性感受。
人成纤维细胞和组织中的信号传导并在小鼠中赋予镇痛作用
具体目标1:阐明位点特异性TRPV 4信号传导差异的作用,以确定新的治疗方法
LPV的目标
具体目标2:探索LPV中炎症、TRPV 4和脂质谱改变之间的关系
患者
具体目标3:使用3D组织培养和体内LPV模型验证TRPV 4和其他已确定的靶点。
对该领域的影响:我们计划实现三个目标:1)确定和验证新的目标,
需要非侵入性和有效的外阴痛治疗,2)提高对外阴痛的理解
机制,以及3)通过关注普遍存在的
信号通路(TRPV 4)被怀疑在疼痛综合征中起作用,靶向它不太可能
导致不良后遗症,包括药物依赖性障碍。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Megan Lindsay Falsetta Wood其他文献
Megan Lindsay Falsetta Wood的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}