Investigating novel mechanisms that underlie glial-mediated synapse elimination in development and aging
Investigating novel mechanisms that underlie glial-mediated synapse elimination in development and aging
批准号:
10721645
负责人:
Taylor Reagan Jay
金额:
$11.24万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-07-15 至 2025-06-30
关键词:
AddressAge-associated memory impairmentAgingBiologicalCD36 geneCell Culture TechniquesDataDevelopmentDevelopmental ProcessDiseaseDrosophila genusEnzyme-Linked Immunosorbent AssayEpilepsyEventExhibitsFunctional disorderGene Expression ProfilingGenesGenetic ScreeningGenetic TranscriptionGoalsImmune systemImmunologic ReceptorsImpairmentLabelLifeLigandsLongevityMaintenanceMammalsMapsMediatingMediatorModelingMolecularNerve DegenerationNervous SystemNervous System PhysiologyNeurodegenerative DisordersNeurodevelopmental DisorderNeurogliaNeuronsPathologicPathologyPathway interactionsPlayProcessProteinsReagentRegulationReporterResearchResearch PersonnelRoleSchizophreniaSignal PathwaySpecific qualifier valueSpecificitySynapsesSystemTechnical ExpertiseValidationVisualizationWorkage relatedage related neurodegenerationautism spectrum disorderbrain healthcandidate identificationcell typedifferential expressionexperimental studyinsightknock-downmouse modelnervous system developmentnovelpostsynapticpresynapticreceptorscreeningsynaptogenesistooltrafficking
中文摘要
项目总结
英文摘要
Project Summary
Formation and maintenance of synaptic connections between appropriate neuronal partners is essential for
proper nervous system function. Indeed, impairments in either initial synapse formation or in subsequent
developmental synapse elimination underlie many neurodevelopmental disorders. Synapse elimination that
occurs outside of appropriate developmental contexts underlies synaptic loss associated with age-related
cognitive decline and in neurodegenerative diseases. Thus, defining the mechanisms that underlie the regulation
of synapse number will provide insight into how appropriate connections are formed during development, and
these pathologies of synapse elimination.
Despite its essential role in nervous system development and function throughout life, we still know little about
the mechanisms underlying this process. We do know, however, that glia are required. In order to identify novel
glial regulators of synapse development, I completed a forward genetic screen in Drosophila, and identified 91
molecules that, when knocked down in glia, alter synapse number. Among these molecules is the immune
receptor Crq, which I found is required for glial elimination of synapses in development. This proposal will focus
on understanding Crq’s role in synapse elimination, in order to gain insight into the larger questions of which
synapses undergo developmental synapse elimination, the mechanisms underlying the specificity of this
process, and whether these same mechanisms are re-used in pathological synapse loss associated with aging.
Aim 1 will address the question of which synapses undergo developmental elimination across the nervous
system and evaluate which of these are Crq-dependent. I have recently developed an inducible pre-synaptic
label that makes this work possible, and will generate inducible postsynaptic labels as part of this aim. Aim 2 will
use proximity labeling to identify the neuronal ligand(s) for Crq that act to specify which synapses undergo
elimination, and will identify how expression and localization of these ligands are regulated. Aim 3 will define
which synapses are lost with aging, and identify whether Crq acts as a common mediator of synaptic loss in
development and aging. I will also perform a targeted screen based on a recent transcriptional profiling
experiment I completed to identify additional glial regulators of age-related synaptic loss.
Together, these studies will address the mechanisms by which synapses are targeted for elimination and how.
This is a key question in achieving the larger goal of understanding how neurons and glia work together to
create and maintain appropriate synaptic connections throughout life. Dissecting these mechanisms will also
provide insight into the process of age-related synaptic loss that underlies age-related cognitive decline. In
addition, performing this work will allow me to address existing gaps in my technical skills that will allow me to
carry out my long-term research goals as an independent invesitigator.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Glial Regulation of Neuronal Physiology in Response to Local Injury
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批准号:10394054
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项目类别:
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资助金额:$0.25万
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负责人:Taylor Reagan Jay
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依托单位:
Glial regulation of neuronal physiology in response to local injury
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项目类别:
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项目类别:
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依托单位:
The role of TREM2 in Alzheimer's disease pathogenesis
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批准号:8783748
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项目类别:
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资助金额:$4.27万
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财政年份:2015
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负责人:Taylor Reagan Jay
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依托单位:
The role of TREM2 in Alzheimer's disease pathogenesis
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批准号:8936326
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项目类别:
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资助金额:$2.92万
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财政年份:2015
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负责人:Taylor Reagan Jay
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依托单位:
海外基金