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