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dc.contributor.authorNguyen, Vienen
dc.contributor.authorSabeur, Khalidaen
dc.contributor.authorMaltepe, Eminen
dc.contributor.authorAmeri, Kuroshen
dc.contributor.authorBayraktar, Omeren
dc.contributor.authorRowitch, Daviden
dc.date.accessioned2018-11-30T00:30:30Z
dc.date.available2018-11-30T00:30:30Z
dc.date.issued2018-04en
dc.identifier.issn1473-4222
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286081
dc.description.abstractThe cerebellum undergoes rapid growth during the third trimester and is vulnerable to injury and deficient growth in infants born prematurely. Factors associated with preterm cerebellar hypoplasia include chronic lung disease and postnatal glucocorticoid administration. We modeled chronic hypoxemia and glucocorticoid administration in neonatal mice to study whole cerebellar and cell type-specific effects of dual exposure. Chronic neonatal hypoxia resulted in permanent cerebellar hypoplasia. This was compounded by administration of Prednisolone as shown by greater volume loss and Purkinje cell death. In the setting of hypoxia and Prednisolone, administration of a small molecule Smoothened-Hedgehog agonist (SAG) preserved cerebellar volume and protected against Purkinje cell death. Such protective effects were observed even when SAG was given as a one-time dose after dual insult. To model complex injury and determine cell type-specific roles for the hypoxia inducible factor (HIF) pathway, we performed conditional knockout of von Hippel Lindau (VHL) to hyperactivate HIF1α in cerebellar granule neuron precursors (CGNP) or Purkinje cells. Surprisingly HIF activation in either cell type resulted in no cerebellar deficit. However, in mice administered Prednisolone, HIF overactivation in CGNPs resulted in significant cerebellar hypoplasia, whereas HIF overactivation in Purkinje cells caused cell death. Together, these findings indicate that HIF primes both cell types for injury via glucocorticoids, and that hypoxia/HIF + postnatal glucocorticoid administration act on distinct cellular pathways to cause cerebellar injury. They further suggest that SAG is neuroprotective in the setting of complex neonatal cerebellar injury.
dc.format.mediumPrinten
dc.languageengen
dc.publisherSpringer Nature
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCerebellumen
dc.subjectPurkinje Cellsen
dc.subjectCells, Cultureden
dc.subjectAnimalsen
dc.subjectMice, Inbred C57BLen
dc.subjectAnimals, Newbornen
dc.subjectMice, Transgenicen
dc.subjectMiceen
dc.subjectHypoxia, Brainen
dc.subjectNervous System Malformationsen
dc.subjectDisease Models, Animalen
dc.subjectCyclohexylaminesen
dc.subjectThiophenesen
dc.subjectPrednisoloneen
dc.subjectMicrofilament Proteinsen
dc.subjectAmino Acids, Dicarboxylicen
dc.subjectCalcium-Binding Proteinsen
dc.subjectNerve Tissue Proteinsen
dc.subjectNeuroprotective Agentsen
dc.subjectAnti-Inflammatory Agentsen
dc.subjectGlucocorticoidsen
dc.subjectDevelopmental Disabilitiesen
dc.subjectCell Proliferationen
dc.subjectGene Expression Regulation, Developmentalen
dc.subjectBasic Helix-Loop-Helix Transcription Factorsen
dc.subjectVon Hippel-Lindau Tumor Suppressor Proteinen
dc.subjectHedgehog Proteinsen
dc.subjectZinc Finger Protein GLI1en
dc.titleSonic Hedgehog Agonist Protects Against Complex Neonatal Cerebellar Injury.en
dc.typeArticle
prism.endingPage227
prism.issueIdentifier2en
prism.publicationDate2018en
prism.publicationNameCerebellum (London, England)en
prism.startingPage213
prism.volume17en
dc.identifier.doi10.17863/CAM.33398
rioxxterms.versionofrecord10.1007/s12311-017-0895-0en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-04en
dc.contributor.orcidBayraktar, Omer [0000-0001-6055-277X]
dc.contributor.orcidRowitch, David [0000-0002-0079-0060]
dc.identifier.eissn1473-4230
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International