. Thelong-termgoalofourresearchistodevelopbetterstrategiestomanipulateinteractionsbetween dystrophicmuscleandtheimmunesystem,sothatthepathologyofDuchennemusculardystrophy(DMD)can bereduced.Asourknowledgeoftheinteractionsbetweentheimmunesystemanddystrophicmusclehas grown,severaldistinctmechanismsthroughwhichimmunecellspromotedamageofdystrophicmusclehave beenidentified.However,wehavealsolearnedthatspecificpopulationsofimmunecells,includingsome macrophagesubpopulationsandregulatoryT-cells,promotemusclegrowthandregenerationinmuscular dystrophy.Becausetheactivation,phenotypeandfunctionofimmunecellsthataffectmusculardystrophyare stronglyinfluencedbycostimulatorysignalsthatareexchangedbetweenmyeloidcellsandlymphoidcells, interventionsthattargetcostimulatorypathwayshavethecapacitytoinfluencethebalancebetween detrimentalandpro-regenerativeprocessesthataremediatedbyimmunecellsindystrophicmuscle. CytotoxicT-lymphocyte-associatedprotein4(CTLA4)isaparticularlyimportantcostimulatorymoleculethat influencesinteractionsbetweenimmunecells.ManipulationofCTLA4availabilitytomediatesignalingbetween myeloidandlymphoidcellsgreatlyinfluencesthemagnitudeandqualityoftheimmuneresponsetodiseased tissue.Ourpreliminaryfindingssupportthehypothesisthatadministrationofarecombinantfusionprotein containingCTLA4profoundlyinfluencestheimmuneresponsetodystrophicmuscleandreducesmuscle damage.Intheinvestigationproposedhere,wewilltestthathypothesis,determinethemechanismsthrough whichCTLA4-mediatedinterventionsaffectmusculardystrophyandevaluatethesafetyandefficacyoflong- termadministrationofexogenousCTLA4inthemdxmousemodelofDMD.
Aim1. TestthehypothesisthattreatmentswithCTLA4-immunoglobinfusionprotein(CTLA4-Ig)producelong- termreductionsinmusclepathologyandimprovefunctioninmousemodelsofDMD.
Aim2. TestthehypothesisthatCTLA4-Igactsonbothlymphoidandmyeloidcellstoreducemuscleinjuryand inflammationandpromoteapro-regenerativeenvironmentindystrophicmuscle.
Aim3. Assesssafetyandlong-termeffectsofCTLA4-Igadministrationonimmunecellfunction. Together,thesefindingscanenableustodeterminewhetherCTLA4-Ig,adrugthatissafeandefficaciousfor thetreatmentofotherhumandiseases,canprovideasuccessful,newstrategyfortreatingDMD.

Public Health Relevance

. Duchennemusculardystrophy(DMD)isaprogressive,lethal,muscle-wastingdiseasethatis influencedbyinteractionsbetweenthediseasedmuscleandtheimmunesystem.Inthis investigation,wewilltestwhethermanipulatingcommunicationsbetweenpopulationsof immunecellsprovidesasafeandeffectivetherapeuticstrategyfortreatingDMD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS109117-02
Application #
10016862
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
Project Start
2019-09-15
Project End
2024-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095