Diseasemodelingwithpatient-derivedinducedpluripotentstemcells(iPSCs)enablesresearcherstoobserve theembryonicdevelopment,maturation,andagingofanycelltypefromthepatient?sbodyinalaboratorypetri dish.Thisnovelandpowerfultechnologythereforeenablesresearcherstocloselyobservethedevelopmentof age-related,lateonsetdiseasesthataffectspecificcellsinthepatientbyreplayingthemoleculareventsthat occurinsidethecellspriortoandduringthedisease.Withthisknowledgeinhand,researcherscanthen designtherapiesbasedonthemoleculardysfunctionsimplicatedincausingthedisease.Ahighlyactivearea ofdiseasemodelingresearchusingiPSCtechnologyisinAmyotrophicLateralSclerosis(ALS),adevastating neurodegenerativedisordercharacterizedbythedeathofmotorneurons,typicallyoccurringinlateadulthood, forwhichthereisnocureandpatientsfaceanaverageofthreeyearsofliferemaining.However,amajor challengecurrentlyfacingthisfieldisthatthemotorneuronsgrownfromiPSCsinthepetridisharemolecularly moresimilartoimmatureembryoniccellsratherthantomatureandagedadultcells.SinceALScausesthe deathofadultratherthanembryonicmotorneurons,anecessarygoalistogeneratematureandagedmotor neuronstostudyinthedish.Byintegratingcomparativegenomic,transcriptomic,andproteomicapproaches proposedinthisapplication,weaimtoidentifythemolecularroadblocksregulatingthepathtothemature motorneuronstate.First,wewillemployacomparativemedicineapproachbetweenmouseandhumancells tofindcommonanddistinctgenesandexpressionnetworksregulatingmotorneurondevelopment,maturation, aging,andALS-induceddegeneration.Thiscomparisonservestocaptureessentialmaturationandaging pathwaysinthemousethatcanhypotheticallybeenactedandacceleratedinhumancells.Second,wewill employasinglecellRNA-sequencingandproteomicapproachtodeeplyandsensitivelydetectpopulationsof maturemotorneuronsvulnerabletoALS.Lastly,wewillintegrateourdatatopredictandexperimentally validateregulatoryfactorscontrollingkeygeneexpressionnetworksiniPSC-derivedmotorneurons.By understandingthecellularsystemscontrollingthematurationandagingprocesses,wecanthendevelop strategiestoacceleratemotorneuronmaturationandaginginthedish,andtherebyfaithfullyreproducethe lateonsetmoleculareventsleadingtothedegenerationofmotorneuronsinALS.

Public Health Relevance

AmyotrophicLateralSclerosis(ALS),adevastatingneurodegenerativedisordercharacterizedbythedeathof motorneurons,typicallyoccurringinlateadulthood,forwhichthereisnocureandpatientsfaceanaverageof threeyearsofliferemaining.CurrenttechnologiestostudyALSwithstemcellmodelsofmotorneuronsgrown inthepetridisharelimited,becausethesecellsarenotmaturingandaginglikethemotorneuronsdyingin adultALSpatientsorlikeinmousemodels.Itisthereforenecessarytofigureoutthemolecularevents happeninginhumanandmousemotorneuronsthatcausethemtoage,sothathumanstemcellmodelsof ALScansuccessfullyreplaythediseaseforresearchertostudyinthepetridishanddeveloptherapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Career Transition Award (K99)
Project #
5K99AG056678-02
Application #
9551485
Study Section
Neuroscience of Aging Review Committee (NIA)
Program Officer
Wise, Bradley C
Project Start
2017-09-01
Project End
2019-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Keenan, Alexandra B; Jenkins, Sherry L; Jagodnik, Kathleen M et al. (2018) The Library of Integrated Network-Based Cellular Signatures NIH Program: System-Level Cataloging of Human Cells Response to Perturbations. Cell Syst 6:13-24
Sances, Samuel; Ho, Ritchie; Vatine, Gad et al. (2018) Human iPSC-Derived Endothelial Cells and Microengineered Organ-Chip Enhance Neuronal Development. Stem Cell Reports 10:1222-1236