Corticospinal Tract Development in Intrauterine Growth Restriction
宫内生长受限时皮质脊髓束的发育
基本信息
- 批准号:10591594
- 负责人:
- 金额:$ 16.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:2&apos,3&apos-Cyclic-Nucleotide Phosphodiesterases3-DimensionalAccelerationAdultAffectAnatomyBiochemicalBioinformaticsBiomedical EngineeringBiometryBirth WeightBrainBrain InjuriesBrain StemBrain regionCardiopulmonaryCell DeathCellsCerebral PalsyCerebrumCorticospinal TractsDemyelinationsDevelopmentDiffusionDiffusion Magnetic Resonance ImagingDistalDown-RegulationDyskinetic syndromeElectromyographyEnvironmentExposure toExtensorFacultyFetal GrowthFetal Growth RetardationFiberFlexorFoundationsFutureGaitGenesGeneticGenetic TranscriptionGestational AgeHumanHyperoxiaHyperreflexiaImageImaging TechniquesImpairmentInfantInjuryInvestigationJointsKnowledgeLearningLesionLimb structureLocomotionMagnetic Resonance ImagingManuscriptsMentorsMentorshipMessenger RNAMethodsModelingModificationMorbidity - disease rateMotorMovementMusMuscleMyelinNervous System TraumaNeurologicOligodendrogliaOntologyPathologicPathway interactionsPerinatalPerinatal Brain InjuryPhenotypePhysical therapyPositioning AttributePredispositionPregnancyPreparationRNARecording of previous eventsResearchResearch PersonnelRiboTagRibosomesRiskSpasmSpastic Cerebral PalsySpinal CordTechnical ExpertiseTechniquesTestingTherapeutic InterventionThromboxane A2TimeTranscriptdifferential expressionimaging modalityin vivoin vivo imaginginnovationinsightkinematicslimb movementmortality riskmotor deficitmotor disordermotor impairmentmouse modelmyelinationnegative affectneonatal patientneonateneuromuscularneuromuscular functionnext generation sequencingnovelnovel therapeutic interventionpostnatalresponsetranscriptometranscriptomicswhite matterwhite matter injury
项目摘要
Project Summary
Infants born following intrauterine growth restriction (IUGR) are at risk for the development of cerebral
palsy (CP). However, it is not precisely understood how perinatal neurologic injury due to IUGR results in
motor dysfunction. Using a novel thromboxane A2 (TXA2) murine model of IUGR, we have previously
demonstrated significant downregulation of major myelin genes (MoBP, PLP1, CNPase, MOG) in whole brain,
decreased corticospinal tract (CST) volume in the brain, and impaired gait. The most profound injury occurred
when IUGR was combined with postnatal hyperoxia exposure, suggesting a “double hit” mechanism. These
findings support a model in which transcriptional changes occur after IUGR that alter oligodendrocytes (OL)
making them more susceptible to hyperoxia. Our findings lead us to the central hypothesis that IUGR with
postnatal hyperoxia results in cell specific changes to the OL transcriptome that lead to pathologic changes to
the CST and motor deficits seen in CP. In Aim 1, in vivo genetic and biochemical methods will be employed in
this model to determine how IUGR/postnatal hyperoxia change the OL transcriptome. This aim will add further
understanding to the underlying causes of white matter (WM) injury after IUGR. As CST is known to be
disturbed in spastic CP, the most common type of CP in perinatal brain injury, Aim 2 will evaluate CST
development using advanced in vivo imaging techniques to demonstrate how IUGR/postnatal hyperoxia alter
development of descending motor tracts in the spinal cord. In Aim 3, altered motor input resulting in distal limb
movement abnormalities and increased hyperreflexia/ spasms will be quantified using novel motor tests. The
innovative motor testing employed in this aim will provide the means to rigorously quantify motor dysfunction
resulting from our injury model and compare it to motor dysfunction seen in CP.
This study will impact the field by 1) providing insight into specific changes to the OL transcriptome
leading to abnormal myelination and CST development and 2) expanding the understanding of the
development of the CP phenotype in IUGR. This study is significant because of its quantitative approach to
imaging modalities and motor assessments that can be applied more broadly to other murine models of
perinatal brain injury and provide a basis for investigating novel therapeutic interventions in humans. Finally,
this study will provide an excellent vehicle for the applicant to develop into an independent investigator.
Investigations will be performed in an environment with an established history of successful mentorship of
junior faculty to independence. With the support of this application, the applicant will 1) advance her technical
skills (RiboTag RNA isolation, next generation sequencing, murine MRI, electromyography and kinematic
testing techniques) and 2) learn advanced biostatistics. Future independent studies will focus on the interplay
between pathways altered by IUGR/hyperoxia in WM development and potential therapeutic interventions that
can be directly tested in the murine models and ultimately neonatal patients.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jill Chang其他文献
Jill Chang的其他文献
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{{ truncateString('Jill Chang', 18)}}的其他基金
Corticospinal Tract Development in Intrauterine Growth Restriction
宫内生长受限时皮质脊髓束的发育
- 批准号:
10672052 - 财政年份:2022
- 资助金额:
$ 16.08万 - 项目类别:
Corticospinal Tract Development in Intrauterine Growth Restriction
宫内生长受限时皮质脊髓束的发育
- 批准号:
10396506 - 财政年份:2020
- 资助金额:
$ 16.08万 - 项目类别: