CurrentestimatesfortheannualtreatmentofUTIsintheUSincludingrecurrencesandtheir complicationsexceed$3.5billion.AsignificantnumberofUTIsarerecurrent(recUTIs),withthe samesubjectexperiencingmultipleboutsofinfection.AfrequentoutcomeofrecUTIsislossin bladdercontrolwhichismanifestedasincreasedurgencyandfrequencyaccompaniedbyloss ofbladdercapacity.Inspiteoftheseverediscomfortandanxietyassociatedwiththiscondition, theunderlyingbasisforbladderimpairmenthasremainedunresolved.Inanexperimental mousemodelofUPEC-inducedrecUTIs,weobservedexuberantsproutingofsensoryand sympatheticnerveswasobservedinthemousebladder,whichcloselyparalleledincreased bladderfrequencyandreducedbladdercapacityintheinfectedmice.Theseobservations suggestthatbladdernervefibersactivelyrespondtobacterialinfectionsandtheseresponses couldpotentiallycontributetolossofbladderdysfunction.Sinceaknowndeterminantofnerve cellssproutinginthebladderisnervegrowthfactor(NGF)welookedforpossiblesourcesofthis growthfactor.Wehaveidentifiedmastcells(MCs)andmonocytesasputativecellularsources ofNGFasmicesubjectedtorecUTIscontainlargenumberofrecruitedmonocytescomparedto navemiceandMCdeficientmicedonotanylossofbladdercontrolevenafterrecUTIs. Therefore,wehypothesizethatthelossofbladdercontrolafterrecUTIs,isthedirectresultof nervefiberhyperplasiawhichisinducedbyNGFandotherneurotrophicfactorsproducedby localMCsandMCrecruitedmonocytes.Wefurtherhypothesizethatitispossibletoprevent lossofbladdercontrolinmicesubjectedtorecUTIsbytherapeutictargetingofNGFandother neurotrophicfactors.Tovalidatethesenotions,wehaveproposedthefollowingspecificaims:(i) Establishaclearlinkbetweenneuronalsproutingandlossofbladdercontrolinmicesubjected torecUTIs;?(iii)ExaminetheroleofneurotrophicfactorsinbladderdysfunctionfollowingrecUTIs andtheeffectoftargetingthesefactorstoprotectandevenreversebladderdysfunction(iii) InvestigatethecontributionofMCstoneuronalsproutingandbladderimpairment.
The underlying basis for the loss of bladder control associated with recurrent urinary tract infection remains unknown. Here we plan to investigate if this loss in bladder function is due to exuberant outgrowth of nerve fibers and if inhibiting this nerve growth has any therapeutic potential.
