ProjectAbstract Oldageisthesinglegreatestriskfactorformanydiseasesincludingperiodontaldisease,dementia, diabetes,andheartdisease.Agingisassociatedwithfailuretomaintainhomeostasis,andoneresultisthe senescenceoftheimmunesystem,whichresultsin?inflammaging.?Bydelayingorreversingthebiological agingprocesses,suchasinflammaging,itmaybepossibletoreducetheimpactofage-relateddiseases, whichcouldhaveprofoundbenefitsforqualityoflife. ThemechanisticTargetofRapamycin(mTOR)hasbeenestablishedasanevolutionarilyconserved regulatoroflongevitythroughstudiesshowingthatreducingmTORactivityextendlifespanandimprove healthspanininvertebratesandmice.Rapamycin,aspecificinhibitorofmTOR,isapromisingcandidatefor delayingage-relateddiseasesandmayact,atleastinpart,byreducinginflammaging.Anage-associated inflammatorydiseaseintheoralcavityisperiodontaldisease.RecentepidemiologicdataintheU.S.revealed 64%ofadultsaged65yearsandolderhadperiodontitis.Hereweproposetotestthehypothesisthat mTORhyperactivationduringagingleadstoimmunecellsenescence,inflammation,andultimately leadstodetrimentalchangestotheoralmicrobiomethatunderliesoralpathologyduringaging. ThiswillbeaccomplishedfirstbyassessingmTORsignalingintheperiodontiumduringagingthrough quantificationofphosphorylationofmTORpathwaycomponentsandinflammatorymarkers.Todetermineif theperiodontiumofnormallyagedmiceiscomparabletoaninducedinflammatorystate,comparisonofaged rodentstoaligature-inducedperiodontitismodelwillbecompleted.Inpreliminarystudies,wehaveshownthat age-associatedperiodontalbonelossinmicewasimprovedafterrapamycintreatment.Thus,theabilityof rapamycintoattenuateage-associatedoralpathologyandeffectsoninnateimmuneresponseinligature- inducedperiodontitiswillbeexplored.Furthermore,theconsequenceofagingandmTORinhibitionontheoral microbiomewillbeinvestigated. TheproposedF30projectwasdevelopedtohelpprovideafoundationforanaspiringdentist-scientist andcontributetounderstandingthemechanisticandmolecularbasisforage-associatedchangesinthe periodontium.InvestigatingmTORsignalingintheperiodontium,andunderstandingtheroleofrapamycinin delayinginflammagingintheoralcavitywillhaveasignificantimpactonthefieldsofgeroscienceanddentistry, andcouldpotentiallyyieldmajorimprovementsinpublichealth.Withstronginstitutionalsupportfromthe UniversityofWashingtonandexcellentmentorship,weareconfidentthatthisF30awardwillaidinthebasic sciencesandclinicaltrainingrequiredtobeasuccessfuldentist-scientist.

Public Health Relevance

Agingisassociatedwithchronicinflammationcalledinflammaging,whichcontributestoperiodontaldisease thatafflictsmorethan6outof10peopleovertheageof65.1-6,15Thegoalofthisproposalistodefinethe molecularmechanismsbywhichagingandinflammagingcontributetoperiodontaldiseaseanddeclineinoral health.ThiswillbeaccomplishedbytestingthehypothesisthataberrantsignalingthroughthemTORgrowth promotingpathwaydrivesinflammationintheoralcavityandevaluatingtheimpactofrapamycin,anFDA approvedinhibitorofmTOR,onprogressionofage-associatedperiodontaldiseaseinmice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30DE027254-01
Application #
9391942
Study Section
NIDR Special Grants Review Committee (DSR)
Program Officer
Frieden, Leslie A
Project Start
2017-07-01
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Washington
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
An, Jonathan Y; Darveau, Richard; Kaeberlein, Matt (2018) Oral health in geroscience: animal models and the aging oral cavity. Geroscience 40:1-10
An, Jonathan Y; Quarles, Ellen K; Mekvanich, Surapat et al. (2017) Rapamycin treatment attenuates age-associated periodontitis in mice. Geroscience 39:457-463