Blast-relatedtraumaticbraininjury(TBI)isassociatedwiththedevelopmentofneuropsychiatricinjuries (includingpost-traumaticstressdisorder[PTSD]andmajordepression)amongsoldiersinthewartheatersof IraqandAfghanistan.Treatmentforblast-relatedTBIiscurrentlylimitedtocounselingandpalliativecare.We haveexploredtheeffectsof74.5-kPablastexposuresthatmimicmildTBI(mTBI)inaratmodel.Blast- exposedratsexhibitavarietyofPTSD-likebehavioraltraits,includingincreasedanxiety,enhancedacoustic startle,alteredresponsestoapredatorscent,andalteredcuedfearresponses.Furtherexperimentalevidence indicatesthatthecerebralvasculatureisamaintargetforblastwaves,asacuteandchronicvascular degenerativeprocessesdevelopafterblast-exposures.Previousresearchhasshownthatfibroblastgrowth factor1(FGF1)isastrongangiogenicfactorthatcaninduceneovascularization,capillarybranching,and vascularremodeling.WehavepublishedevidenceindicatingthatFGFsignalingisessentialforendothelialcell homeostasisandsurvival. TheoverallgoaloftheproposedresearchistotestwhetherintranasaladministrationofFGF1can reversetheestablishedcerebrovascularandcognitivedegenerativeprocessespresentinourratmodelof blast-inducedmTBI.WeproposetoadministerrecombinantFGF1intoblast-exposedrats(374.5kPa)once theyhavedevelopedthechronicPTSDphenotype(6monthspost-blastexposure)totestwhetherthis treatmentimprovesthecognitivedeficitsandvascularalterationsassociatedwiththesediseases.Wewilltest formemory(MorrisWaterMaze),contextualandcuedfearconditioning,andnovelobjectrecognition.UsingX- rayCT,immunohistochemicalandstereologicalmethodswewillanalyzealterationsinlargevesselsandinthe microvasculature,includingthepresenceofabnormalvasculatureandchangesinvasculardensity,length,and volume.Biochemicalanalyseswillidentifyanymolecularstructuralchangesinthemicrovasculatureinduced byFGF1treatment. Collectively,theproposedstudieswillexplorethepotentialtherapeuticbenefitsofFGF1forthetreatment of blast-induced PTSD. These studies may uncover new therapeutic options for the treatment of active duty militarypersonnelandveteransaffectedbythisdevastatingcondition.

Public Health Relevance

Blastexposuresareassociatedwiththedevelopmentofbehavioraldysfunctions(includingPTSDand depression)associatedwithalterationsinthecerebralvasculature.Theproposedresearchaimstotest whetherthepro-angiogenicpropertiesoffibroblastgrowthfactor1(FGF1)canreversethevascularand cognitivedysfunctionsinaratmodelofblast-inducedmTBI.Thefindingsofthisresearchmaybeusedto developeffectivetherapeuticstrategiesforthetreatmentofveteransandsoldiersaffectedbyblast-induced behavioraldysfunctions.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Veterans Administration (I21)
Project #
5I21RX002876-02
Application #
9698191
Study Section
Rehabilitation Research and Development SPiRE Program (RRDS)
Project Start
2018-06-01
Project End
2020-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
James J Peters VA Medical Center
Department
Type
DUNS #
040077133
City
Bronx
State
NY
Country
United States
Zip Code
10468