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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK121969-02
Application #
10128446
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mullins, Christopher V
Project Start
2020-03-16
Project End
2024-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Duke University
Department
Pathology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705