Molecular pathways regulating astrocyte morphogenesis and function
调节星形胶质细胞形态发生和功能的分子途径
基本信息
- 批准号:10454296
- 负责人:
- 金额:$ 49.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:Alexander DiseaseAnimal BehaviorAstrocytesAxonBiological AssayBlood VesselsBrainCell physiologyCellsCellular biologyDataDefectDevelopmentDrosophila genusEndodermEnvironmentEnzymesEpilepsyExhibitsFoundationsFunctional disorderG-Protein-Coupled ReceptorsGTP-Binding Protein alpha Subunits, GsGenesGeneticGenetic ModelsGenetic ScreeningGerm CellsGoalsGrowthHomeostasisHomologous GeneHumanImageIndividualInfiltrationLightLipidsMaintenanceMembraneMolecularMolecular GeneticsMorphogenesisMorphologyMusMutationNeuraxisNeurogliaNeurologicNeuronsNeuropilNeurotransmittersNutrientOrganismOrthologous GenePathway interactionsPhenocopyPhysiologyProcessProtein phosphataseRNA InterferenceRNA interference screenRegulationRoleSignal PathwaySignal TransductionSignaling MoleculeSynapsesVertebratesWorkZebrafishautism spectrum disorderbasebrain cellbrain healthcell growthcell motilitycell typeextracellularflygenetic approachhuman diseasein vivoin vivo imaginginsightionic balanceknock-downlipid phosphate phosphataselive cell imagingmutantnervous system developmentnervous system disorderneural circuitneuronal cell bodynovelsynaptogenesistool
项目摘要
SUMMARY
Astrocytes are the most abundant glial cell type in the human brain and are critical for central nervous system
(CNS) development and function. Mature astrocytes are unusually elaborate cells, with an intricate and
ramified morphology. Their numerous fine cellular processes interact closely with synapses, neuronal cell
bodies, axons, blood vessels, and other glial cells throughout the CNS. Through these interactions, astrocytes
fulfil diverse functions to support and enhance neuronal activity, maintain CNS homeostasis, and modulate
circuits. Underscoring the importance of proper astrocyte development, defects in astrocyte growth or loss of
astrocyte complexity are implicated in many neurological diseases, including Alexander's disease, autism, and
epilepsy. However, it remains poorly understood how astrocytes develop their intricate morphological
associations and regulate neural circuit function.
Our long-terms goals are to understand how astrocyte acquire their remarkable morphology, target their
processes to synapses, and use these cell-cell contacts to modulate brain function. We recently performed a
genetic screen in Drosophila to identify new regulators of astrocyte development, and uncovered a novel gene,
Trapped in endoderm 1 (Tre1), as required for astrocyte morphogenesis. We find that loss of Tre1 leads to
severely reduced astrocyte complexity in vivo, resulting in decreased infiltration of the synaptic neuropil. Tre1
encodes a G protein-coupled receptor (GPCR) with no known function in the CNS. This proposal will use a
synergistic combination of molecular-genetic tools available in Drosophila and zebrafish along with new tools
we have generated and in vivo imaging to: determine how Tre1 regulates astrocyte morphogenesis, function,
and animal behavior in Drosophila (Aim 1); elucidate signaling pathways upstream and downstream of Tre1
activation (Aims 1+2); and define the evolutionary conservation of Tre1 in vertebrates (Aim 3). Our work will
provide exciting new insights into the mechanisms regulating astrocyte development and function in vivo and
lay the foundation for understanding astrocyte growth and dysfunction in human disease.
摘要
星形胶质细胞是人脑中含量最丰富的胶质细胞类型,对中枢神经系统至关重要。
(CNS)发展和功能。成熟的星形胶质细胞是异常精细的细胞,具有错综复杂的
分枝形态。它们众多的细微细胞突起与突触、神经细胞
中枢神经系统中的小体、轴突、血管和其他神经胶质细胞。通过这些相互作用,星形胶质细胞
发挥多种功能以支持和增强神经元活动,维持中枢神经系统的动态平衡,并调节
电路。强调星形胶质细胞正常发育的重要性,星形胶质细胞生长缺陷或丧失
星形胶质细胞的复杂性与许多神经系统疾病有关,包括亚历山大病、自闭症和
癫痫。然而,星形胶质细胞如何发展其复杂的形态仍然知之甚少。
联想和调节神经回路功能。
我们的长期目标是了解星形胶质细胞如何获得其非凡的形态,靶向其
突触的过程,并利用这些细胞-细胞接触来调节大脑功能。我们最近表演了一场
在果蝇中进行基因筛查,以确定星形胶质细胞发育的新调节因素,并发现了一个新的基因,
被困于内胚层1(Tre1),这是星形胶质细胞形态发生所必需的。我们发现失去Tre1会导致
严重降低了体内星形胶质细胞的复杂性,导致突触神经纤维的渗透减少。Tre1
编码一个在中枢神经系统中未知功能的G蛋白偶联受体(GPCR)。此提案将使用
果蝇和斑马鱼可用的分子遗传工具与新工具的协同组合
我们已经产生并在体内成像:确定Tre1如何调节星形胶质细胞的形态发生、功能、
和果蝇的动物行为(目标1);阐明Tre1上游和下游的信号通路
激活(目标1+2);并定义脊椎动物Tre1的进化保守性(目标3)。我们的工作将
为调节星形胶质细胞体内发育和功能的机制提供了令人兴奋的新见解
为了解人类疾病中星形胶质细胞的生长和功能障碍奠定基础。
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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Marc R Freeman其他文献
Neuronal death or dismemberment mediated by Sox14
由 Sox14 介导的神经元死亡或肢解
- DOI:
10.1038/nn1209-1479 - 发表时间:
2009-12-01 - 期刊:
- 影响因子:20.000
- 作者:
Jeannette M Osterloh;Marc R Freeman - 通讯作者:
Marc R Freeman
Marc R Freeman的其他文献
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{{ truncateString('Marc R Freeman', 18)}}的其他基金
2023 Glial Biology: Functional Interactions Among Glia and Neurons Gordon Research Conference and Gordon Research Seminar
2023年胶质细胞生物学:胶质细胞和神经元之间的功能相互作用戈登研究会议和戈登研究研讨会
- 批准号:
10609354 - 财政年份:2022
- 资助金额:
$ 49.07万 - 项目类别:
Molecular pathways regulating astrocyte morphogenesis and function
调节星形胶质细胞形态发生和功能的分子途径
- 批准号:
10645162 - 财政年份:2021
- 资助金额:
$ 49.07万 - 项目类别:
Molecular pathways regulating astrocyte morphogenesis and function
调节星形胶质细胞形态发生和功能的分子途径
- 批准号:
10316938 - 财政年份:2021
- 资助金额:
$ 49.07万 - 项目类别:
How do non-myelinating glia ensheath axons?
非髓鞘神经胶质细胞如何包裹轴突?
- 批准号:
10617726 - 财政年份:2019
- 资助金额:
$ 49.07万 - 项目类别:
How do non-myelinating glia ensheath axons?
非髓鞘神经胶质细胞如何包裹轴突?
- 批准号:
10397991 - 财政年份:2019
- 资助金额:
$ 49.07万 - 项目类别:
Characterizing new genes that govern mitochondrial function in the axon
表征控制轴突线粒体功能的新基因
- 批准号:
9272960 - 财政年份:2016
- 资助金额:
$ 49.07万 - 项目类别:
Characterizing new genes that govern mitochondrial function in the axon
表征控制轴突线粒体功能的新基因
- 批准号:
9168491 - 财政年份:2016
- 资助金额:
$ 49.07万 - 项目类别:
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