Mechanisms of oligodendroglial ciliary function in white matter injury repair
少突胶质细胞纤毛功能在白质损伤修复中的机制
基本信息
- 批准号:10659990
- 负责人:
- 金额:$ 40.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-15 至 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdultAffectAgonistAreaBiologicalBlood VesselsCREB1 geneCatalogsCell CommunicationCell Culture TechniquesCell ProliferationCellsCellular biologyCentral Nervous System DiseasesCerebral PalsyCiliaCollaborationsCuesCyclic AMPDataDemyelinationsDevelopmentDiseaseDisease ProgressionEnzymesErinaceidaeFailureG-Protein-Coupled ReceptorsGene ExpressionGene TargetingGenesGrantHomeostasisHumanImageIn VitroInjuryLabelLesionLettersLoxP-flanked alleleMammalian CellMapsMediatingMethodsMicrotubulesMultiple SclerosisMultiple Sclerosis LesionsMusMyelinMyelin SheathNatural regenerationNatureNeurologic DysfunctionsOrganellesPathway interactionsPericytesPopulationProliferatingProteinsProteomeRegulationRestRoleSignal PathwaySignal TransductionSignaling MoleculeSiteSliceSpinal CordSurveysTechniquesTissuesTransducersTransgenic OrganismsVisualizationcell behaviorcell typehypoxia neonatorumin vivoinjury and repairinsightmRNA sequencingmigrationneonatal humannervous system disordernewborn brain injuryoligodendrocyte precursoroligodendrocyte progenitorpharmacologicprecursor cellprogenitorprogramsrecruitremyelinationrepairedresponseresponse to injurystem cellstherapeutic targettoolwhite matterwhite matter injury
项目摘要
PROJECT ABSTRACT
After damage to white matter tracts (WMI) in CNS diseases such as multiple sclerosis (MS) in adults and
newborn brain injuries that cause cerebral palsy (CP), myelin sheaths can be regenerated by activated
oligodendrocyte precursor cells (OPCs). Failure of this remyelination program often occurs due to the improper
recruitment of OPCs into injury sites, contributing significantly to ongoing neurological dysfunction and disease
progression. Understanding the mechanisms controlling OPC biology during remyelination will provide insights
as to why myelin repair fails in human cases. Importantly, OPCs dynamically produce primary cilia, microtubule-
based organelles that transduce intercellular cues in a specialized signaling compartment. The role of primary
cilia in regulating developmental pathways in OPCs remains poorly understood. Here, we show that OPCs
require primary cilia to respond properly to WMI. First, this grant will demonstrate that genetically removing
primary cilia from OPCs results in inadequate WMI repair, identifying the primary cilium as a critical
effector of biological change in OPCs necessary for the WMI response. Furthermore, as there remains little
mechanistic understanding of ciliary signaling pathways in OPCs, we will use a combination of approaches that
ultimately define a GPCR/cAMP/CREB signaling axis beginning at the primary cilium as a crucial regulator
of OPC biology. Finally, with recent advances in proximity-labeling, we can now catalogue the proteins that
survey OPC primary cilia using a technique termed cilia-APEX. This grant will utilize cilia-APEX to identify
signaling molecules that localize to OPC primary cilia in vitro and during remyelination in vivo. This will
demonstrate dynamic changes in the protein content of OPC primary cilia during different stages of
remyelination, while also adding significant insight into the extent of ciliary functions in OPCs. Together, these
studies will show that primary cilia are a critical signaling module in OPCs for the regulation of remyelination,
and will reveal potential therapeutic target for conditions such as MS and CP, where the OPC response to injury
can be dysfunctional.
1
项目摘要
在成人多发性硬化症(MS)等中枢神经系统疾病中白质束(WMI)受损后,
新生儿脑损伤导致脑瘫(CP),髓鞘可通过激活再生
少突胶质前体细胞(OPC)。这种髓鞘再生计划的失败经常是由于不适当的
将OPC招募到损伤部位,大大促进了持续的神经功能障碍和疾病
进步。了解在髓鞘再生过程中控制OPC生物学的机制将提供深入的见解
为什么髓鞘修复在人类病例中失败。重要的是,OPC动态地产生初级纤毛,微管-
在一个专门的信号室中传递细胞间信号的细胞器。初级教师的角色
纤毛在调节OPC的发育途径中的作用仍然知之甚少。在这里,我们向您展示OPC
要求初级纤毛对WMI做出正确反应。首先,这笔赠款将证明从基因上移除
OPC的初级纤毛导致WMI修复不充分,确定初级纤毛是关键
WMI反应所必需的OPC中生物学变化的效应因子。此外,由于几乎没有
从机制上理解OPC中的纤毛信号通路,我们将使用以下方法的组合
最终确定从初级纤毛开始的GPCR/cAMP/CREB信号轴是一个重要的调节因子
OPC生物学的。最后,随着邻近标记技术的最新进展,我们现在可以对
使用一种名为纤毛-APEX的技术测量OPC主纤毛。这笔赠款将利用Cilia-APEX来识别
在体外和体内重新髓鞘形成过程中定位于OPC初级纤毛的信号分子。这将是
显示OPC初级纤毛在不同发育阶段蛋白质含量的动态变化
重新髓鞘形成,同时也增加了对OPC纤毛功能范围的显著洞察。加在一起,这些
研究表明,初级纤毛是OPC中调节重新髓鞘形成的关键信号模块,
并将揭示MS和CP等疾病的潜在治疗靶点,在这些情况下,OPC对损伤的反应
可能会出现功能障碍。
1
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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Stephen Philip James Fancy其他文献
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{{ truncateString('Stephen Philip James Fancy', 18)}}的其他基金
Astrocytes control the termination of oligodendrocyte precursor cell perivascular migration during CNS development
星形胶质细胞控制中枢神经系统发育过程中少突胶质细胞前体细胞血管周围迁移的终止
- 批准号:
10727537 - 财政年份:2023
- 资助金额:
$ 40.38万 - 项目类别:
Oligodendroglial Intrinsic Ring Finger Protein family members are injury specific, but not developmental, regulators of oligodendrocyte maturation
少突胶质细胞固有环指蛋白家族成员是损伤特异性的,但不是发育性的少突胶质细胞成熟的调节因子
- 批准号:
10239257 - 财政年份:2020
- 资助金额:
$ 40.38万 - 项目类别:
Vasculature provides the substrate for oligodendrocyte progenitor migration in development and disease
脉管系统为少突胶质细胞祖细胞在发育和疾病中迁移提供基质
- 批准号:
9309564 - 财政年份:2017
- 资助金额:
$ 40.38万 - 项目类别:
Vasculature provides the substrate for oligodendrocyte progenitor migration in development and disease
脉管系统为少突胶质细胞祖细胞在发育和疾病中迁移提供基质
- 批准号:
10115137 - 财政年份:2017
- 资助金额:
$ 40.38万 - 项目类别:
Project 2: Mechanisms underlying oligodendrocyte precursor-mediated angiogenesis and interneuron vessel-associated migration in human neonatal brain
项目2:人类新生儿脑中少突胶质细胞前体介导的血管生成和中间神经元血管相关迁移的机制
- 批准号:
10627968 - 财政年份:2014
- 资助金额:
$ 40.38万 - 项目类别:
Project 2: Mechanisms underlying oligodendrocyte precursor-mediated angiogenesis and interneuron vessel-associated migration in human neonatal brain
项目2:人类新生儿脑中少突胶质细胞前体介导的血管生成和中间神经元血管相关迁移的机制
- 批准号:
10221062 - 财政年份:2014
- 资助金额:
$ 40.38万 - 项目类别:
Project 2: Mechanisms underlying oligodendrocyte precursor-mediated angiogenesis and interneuron vessel-associated migration in human neonatal brain
项目2:人类新生儿脑中少突胶质细胞前体介导的血管生成和中间神经元血管相关迁移的机制
- 批准号:
10408734 - 财政年份:2014
- 资助金额:
$ 40.38万 - 项目类别:
Project 2: Mechanisms underlying oligodendrocyte precursor-mediated angiogenesis and interneuron vessel-associated migration in human neonatal brain
项目2:人类新生儿脑中少突胶质细胞前体介导的血管生成和中间神经元血管相关迁移的机制
- 批准号:
10023629 - 财政年份:
- 资助金额:
$ 40.38万 - 项目类别:
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