Pediatriccardiacarrestaffects10-?15,000childreneachyear.Fewerthan1in10children survive,andthemajorityofdeathsoccurduetosevereneurologicinjury.Atpresent,no therapyexistsforbraininjuryinchildrenaftercardiacarrest,andnewapproachesareneeded. Thecurrentproposalfocusesononeunder-?appreciatedaspectofbraininjuryaftercardiac arrest?injurytolong-?rangeaxons.Usingaclinically-?realisticmodelofseverepediatriccardiac arrestandresuscitationinimmaturerats,wehavegeneratednewpreliminarydatashowing thataxonalinjuryoccursearlyafterresuscitationandisassociatedwithdepletionof nicotinamideadeninedinucleotide(NAD+)specificallyinthewhitematter.Weproposethatthe mechanismofaxonalNAD+depletionaftercardiacarrestinvolvesinjury-?dependentactivation oftheproteinSARM1.SARM1istheonlyknowninjury-?activatedNAD-?cleavingenzymein axons,anditsactivationeffectsaxonaldegenerationinseveralinjuryparadigms.Todetermine theroleofSARM1inpost-?arrestaxonalinjurywhilepreservingtheclinicalrealismofthe cardiacarrestmodelindevelopingrats,wegeneratedSARM1knockout(SARM1-?/-?)rats.Our centralhypothesisisthatSARM1-?mediatedNAD+depletioncontributestoaxonalinjuryand poorneurologicoutcomesafterpediatriccardiacarrest.WeproposethreeSpecificAimstotest ourhypothesis.
In Aim1, wewilldeterminewhetherSARM1deletiona)preventswhitematter NAD+depletionandb)preservesaxonalfunctionandstructureaftercardiacarrest.
In Aim2, we willdeterminewhetherSARM1deletionimprovesmotorbehavioraloutcomesaftercardiac arrest.
In Aim3, wewilldetermineifnicotinamideriboside?asafeNAD+precursorthat penetratestheblood-?brainbarrier?maintainsNAD+levelsandimprovesmotorbehaviorafter cardiacarrest.Ifsuccessful,theproposedexperimentswillidentifySARM1activationandNAD+ depletionasmechanismscontributingtoaxonalinjuryaftercardiacarrestandestablishapre-? clinicalbasisforanoveltherapeuticapproachtoadevastating,andcurrentlyuntreatable, neurologicinjuryinchildren.
Braininjuryinchildrenaftercardiacarrestiscommon,severeandcostly.Currently,thereisno effectivetreatment.Thisprojectintegratesmetabolic,physiologic,imagingandbehavioral studiesintoamultiprongedapproachtoevaluateanovelmechanismandtherapeuticapproach tobraininjuryinchildrenaftercardiacarrest.