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.
Public Health Relevance Statement
PROJECT NARRATIVE
Localized provoked vulvodynia (LPV) is a common cause of painful intercourse in women of reproductive age,
but therapy options short of surgery are limited and marginally effective and patients may suffer for months to
years before finding relief, if ever. We have identified new targets for LPV therapy that are likely involved in
other pain conditions and that could lead to a breakthrough in analgesic therapy. In the wake of the opioid
epidemic, it is imperative that we develop new, effective, and safe pain therapies to replace current
medications that result in dependence.
NIH Spending Category
No NIH Spending Category available.
Project Terms
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 MeasurementPain ThresholdPain managementPainlessPathway interactionsPatientsPerceptionPersistent painPharmaceutical PreparationsPlayPremenopauseProcessProductionQuality of lifeQuantitative Reverse Transcriptase PCRReporterReproducibilityRiskRoleSensorySerotoninSignal PathwaySignal TransductionSiteSmall Interfering RNAStimulusSyndromeTamponsTechniquesTemperatureTherapeutic InterventionTissuesTopical applicationTouch sensationUnited States National Institutes of HealthVaginaVestibuleVulvaVulvodyniaWalkingWestern BlottingWomanWomen's 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
Eunice Kennedy Shriver National Institute of Child Health and Human Development
CFDA Code
865
DUNS Number
041294109
UEI
F27KDXZMF9Y8
Project Start Date
21-September-2023
Project End Date
31-May-2028
Budget Start Date
01-June-2024
Budget End Date
31-May-2025
Project Funding Information for 2024
Total Funding
$575,316
Direct Costs
$415,694
Indirect Costs
$159,622
Year
Funding IC
FY Total Cost by IC
2024
Eunice Kennedy Shriver National Institute of Child Health and Human Development
$575,316
Year
Funding IC
FY Total Cost by IC
Sub Projects
No Sub Projects information available for 5R01HD108173-02
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