Abstract

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.

Public Health Relevance

Braininjuryinchildrenaftercardiacarrestiscommon,severeandcostly.Currently,thereisno effectivetreatment.Thisprojectintegratesmetabolic,physiologic,imagingandbehavioral studiesintoamultiprongedapproachtoevaluateanovelmechanismandtherapeuticapproach tobraininjuryinchildrenaftercardiacarrest.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS112294-01
Application #
9800318
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
2019-09-01
Project End
2024-05-31
Budget Start
2019-09-01
Budget End
2020-05-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010