Molecular Regulators of Synaptic Specificity
突触特异性的分子调节剂
基本信息
- 批准号:10581824
- 负责人:
- 金额:$ 0.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-02 至 2023-08-29
- 项目状态:已结题
- 来源:
- 关键词:AdoptedAffectAfferent NeuronsAnimal ModelArchitectureAxonBehaviorBehavioralBehavioral AssayBiological AssayBrainCaenorhabditis elegansCellsCloningComplexComputer softwareDatabasesDefectDendritesDevelopmentElectronic Medical Records and Genomics NetworkEnvironmentExcisionGene ExpressionGenesGeneticGenetic ScreeningGenomeGoalsIndividualInstinctLabelLife Cycle StagesLinkLocomotionMaintenanceMammalsMapsMethodsModelingMolecularMolecular AnalysisMolecular CloningMorphogenesisMovementMutagenesisMutationNervous system structureNeurodevelopmental DisorderNeuronsNociceptionNociceptorsOrangesOutputPathway interactionsPatternPhenotypeProcessProteinsRNA InterferenceReproducibilityResearchRoleSiteSpecificitySynapsesTestingTo specifyVideo RecordingWorkautism spectrum disorderbehavior testdesignexpectationgenetic analysisgraspin vivolive cell imagingmeetingsmutantmutation screeningnervous system disordernew therapeutic targetnoveloptogeneticspostsynapticprogramsreconstitutionresponsestemsynaptogenesistooltranscription factortranscriptome sequencing
项目摘要
Project Summary
Specific circuits in the brain determine how we sense and respond to our environment. These highly connected
networks emerge during development as neurons extend projections to defined meeting sites, identify partners,
and begin synaptogenesis. Although initial connections may be modified later, the overall pattern of connectivity
is predictable thus suggesting that partner selection can be encoded by the genome. It follows that genetic
analysis can be powerfully employed to find synaptic specificity genes by identifying mutants with altered patterns
of connectivity. With the goal of identifying novel, conserved target selection proteins, I will screen for mutations
that disrupt distinctive behaviors that depend on neuron-specific synapses in C. elegans. This work focuses on
the PVD sensory neuron and its synaptic targets, PVC and AVA. PVD stimulation activates PVC, its dominant
partner, and triggers forward movement. If the PVC connection is removed, however, AVA is activated instead,
resulting in reverse locomotion. Thus, mutants that selectively disrupt either PVD→PVC or PVD→AVA
connections can be identified from readily distinguished behaviors (e.g., forward vs reverse movement). With its
short life cycle and powerful genetic tools, C. elegans is especially useful for unbiased genetic screens. In Aim
1 I will use an optogenetic strategy to activate PVD in a forward genetic EMS mutagenesis screen that uses a
high-throughput video recording system (WormLab) to identify mutants with selectively altered locomotion.
Behavioral mutants with these specific locomotory phenotypes will be screened with GRASP (GFP
Reconstitution Across Synaptic Partners) markers to confirm that either PVD→PVC or PVD→AVA synapses are
disrupted during synaptogenesis. Molecular cloning methods will be used to identify the affected synaptic
specificity genes. Aim 2 adopts an independent approach that stems from the expectation that synaptic
specificity genes in PVD should be regulated by cell autonomous transcription factors (TFs). My strategy exploits
a list of 35 PVD-enriched TFs previously derived from RNA-Seq profiling. I will use RNAi and available genetic
mutants in the GRASP marker assay to test each of these TFs for potential roles in either PVD→PVC or
PVD→AVA synaptogenesis. This TF screen has the advantage of dysregulating multiple target genes
simultaneously for a robust synaptic specificity phenotype. I will use PVD-specific RNA-Seq to identify the targets
of the synapse-specific TFs and then test them individually for roles in PVD synaptic specificity using the
behavioral assay and GRASP markers. Together, these approaches in C. elegans are expected to reveal key
determinants of synaptic specificity that can be tested for conserved roles in more complex nervous systems
and for links to neurological disorders associated with altered synaptogenesis such as Autism Spectrum Disorder
(ASD).
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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Tyler J. Kennedy其他文献
Tyler J. Kennedy的其他文献
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{{ truncateString('Tyler J. Kennedy', 18)}}的其他基金
FMRP and Pumilio co-regulate synaptogenesis by controlling Neuroglian expression
FMRP 和 Pumilio 通过控制 Neuroglian 表达共同调节突触发生
- 批准号:
9068676 - 财政年份:2015
- 资助金额:
$ 0.25万 - 项目类别:
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