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