Abstract

Duchennemusculardystrophy(DMD)isalethal,progressive,muscle-wastingdiseasethatinvolvesdefectsin theregenerativecapacityofthepathologicalmuscle.Inrecentyears,expandingknowledgeofepigenetic mechanismsthatinfluencemusclegrowthandregenerationhasshownthatmanipulatingthosemechanisms canbetherapeuticallyuseful.Thefocusofourstudyistodeterminefactorsthataffecttheexpressionof importantepigeneticregulatorsthatcaninfluencegeneexpressioninskeletalmusclestemcells,called satellitecells.WewilltestthenovelhypothesisthattheproteinKlotho(KL)influencesmyogenesisthroughthe epigeneticregulationofsatellitecellactivationanddifferentiation,therebyaffectingmuscleregeneration.We willinvestigatethisthroughthefollowingaims:
Aim1. DeterminewhetherKLinfluencessatellitecellactivationanddifferentiationthroughchangesinhistone methylation.Wewillassaywhetherdown-regulationofspecifichistonedemethylasesinmuscleisasignificant componentofthemechanismthroughwhichKLaffectssatellitecellproliferationandexpressionofmyogenic regulatorygenes.WewillalsoassayforgenesthatexperiencechangesinhistonemethylationatH3K27in musclecellsstimulatedwithKL.
Aim2. DeterminewhethermanipulatingKLexpressionaffectshistonemethylationinsatellitecellsfrommdx mice,amodelforDMD.Wewillassayforchangesinnucleartargetingorexpressionofspecifichistone demethylasesthatresultfromgeneticallyrestoringKLexpressiontodystrophic,mdxmice.Wewillalsoassay forgenesexperiencingchangesinH3K27methylation,causedbyKLtransgeneexpressioninmdxmice WeanticipatethatourfindingswillestablishnovelregulatoryrolesforKL,inwhichtheproteinplaysan epigeneticregulatoryrolethataffectsmyogenesis.Furthermore,theresultsfromthisstudycanprovidethe identityofnewtherapeutictargetstotreatDMDbyimprovingmuscleregeneration.

Public Health Relevance

. Duchennemusculardystrophy(DMD)isalethaldiseasethatcausesprogressivemusclewastingandfailed muscleregeneration.Thisinvestigationwillexamineepigeneticregulatorypathwaysthatpromotemuscle regeneration.Theresultsofthisstudywillexpandunderstandingofpathogenicmechansmsinmuscular dystrophyandexposepotentialtherapeutictargetsforthetreatmentofDMD.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31AR071782-01A1
Application #
9542064
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Boyce, Amanda T
Project Start
2018-09-01
Project End
2021-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Physiology
Type
Graduate Schools
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095