Role and Regulation of Neural Stem Cells in Remyelination
神经干细胞在髓鞘再生中的作用和调节
基本信息
- 批准号:10155591
- 负责人:
- 金额:$ 42.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-06-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAdultAreaAstrocytesAxonBrainCellsChronicComplement 1qComplexCorpus CallosumDemyelinating DiseasesDemyelinationsEffectivenessFutureGeneticGenetic EnhancementGoalsInflammationInflammatoryInterneuronsLesionMapsMediator of activation proteinMicrogliaModelingMorbidity - disease rateMultiple SclerosisMyelin SheathNerve FibersNeurogliaOligodendrogliaPathologicPatientsPharmacologyPhenotypeRecoveryRecovery of FunctionResearchRoleSHH geneSecondary toSeriesSignal TransductionSiteSourceTherapeuticTranscriptcell typeimprovedinsightnerve stem cellnervous system disorderneural recruitmentneuroregulationnovelolfactory bulboligodendrocyte lineageoligodendrocyte progenitorprecursor cellpreventrecruitremyelinationrepairedstemstem cell expansionstem cellssubventricular zonetherapy developmenttranscription factortranscriptome sequencingwhite matter
项目摘要
Project Summary
Both oligodendrocyte progenitors (OPCs) and neural stem cells (NSCs) in the subventricular zone (SVZ)
are known sources of remyelinating oligodendrocytes. Their precise contribution to remyelination and
what limits their effectiveness in repair are active areas of research with important therapeutic
implications. We have found that Sonic hedgehog (Shh)-responsive adult NSCs are a significant source
of remyelinating cells. These NSCs, which are enriched in the ventral SVZ, normally give rise to
parenchymal astrocytes and interneurons. They only enter white matter tracts upon demyelination,
including to the the demyelinated corpus callosum (CC), where they are robustly recruited and
differentiate preferentially into oligodendroglia. Unexpectedly, their recruitment to such lesions and their
differentiation into remyelinating oligodendrocytes is significantly enhanced by genetic ablation or
pharmacological inhibition of the Shh-dependent transcription factor Gli1. Further, pharmacological
inhibition of Gli1 enhances remyelination in the adult and improves functional recovery from
inflammatory demyelination. Important questions include whether their contribution to remyelination is
impacted by competition with parenchymal OPCs during repair, what recruits these cells to demyelinated
lesions, and how Gli1 limits NSC repair. In Aim 1, we examine whether NSCs expand their contribution
to repair if OPC remyelination is blocked to assess whether NSC and OPCs compete to remyelinate the
same lesion sites. In Aim 2, we assess the role of microglia (MG) and astrocytes, which are both
activated in lesion sites, in the expansion and recruitment of NSCs. Our preliminary studies suggest MG
are essential for NSC expansion and recruitment but do not indicate if this is a direct effect or is
secondary to activation of astroglia. In Aim 3, we will investigate a novel NSC phenotype revealed by
RNAseq that is only upregulated with demyelination and is Gli1- dependent. This phenotype includes a
number of inflammation-related mediators and the C1q complex. We will characterize this altered NSC
phenotype further, examine its potential role in regulating the number and phenotype of MG in the SVZ,
and assess its potential impact on NSC clearance and remyelination. These studies will provide
important, new insights into the signals (cells and molecules) that regulate the contribution of stem cells
to repair and may thereby guide therapeutic efforts to promote remyelination.
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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JAMES SALZER其他文献
JAMES SALZER的其他文献
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{{ truncateString('JAMES SALZER', 18)}}的其他基金
Impact of Schwann Cell Pathology on Axon Structure and Function
雪旺细胞病理学对轴突结构和功能的影响
- 批准号:
10568051 - 财政年份:2022
- 资助金额:
$ 42.47万 - 项目类别:
Role and Regulation of Neural Stem Cells in Remyelination
神经干细胞在髓鞘再生中的作用和调节
- 批准号:
10412936 - 财政年份:2018
- 资助金额:
$ 42.47万 - 项目类别:
Regulation of Schwann cell enshealthment and myelination by type III Neuregulin 1
III 型神经调节蛋白 1 对雪旺细胞健康和髓鞘形成的调节
- 批准号:
8675621 - 财政年份:2013
- 资助金额:
$ 42.47万 - 项目类别:
2012 Myelin Gordon Research Conference & Gordon Research Seminar
2012年髓磷脂戈登研究会议
- 批准号:
8317793 - 财政年份:2012
- 资助金额:
$ 42.47万 - 项目类别:
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