Cellular and molecular mechanisms of peripheral nerve regeneration
Cellular and molecular mechanisms of peripheral nerve regeneration
批准号:
9293867
负责人:
Michael Granato
金额:
$46.4万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-07-15 至 2017-06-30
关键词:
AddressAdultAffectAnabolismAnimalsAutoimmune DiseasesAxonBasement membraneBehaviorBell PalsyCell Surface ReceptorsCellsDataDevelopmentDiabetes MellitusDorsalExhibitsExtracellular MatrixFaceFacial nerve structureFoundationsGenesGeneticGoalsGrowthGrowth ConesHealedHeparan Sulfate BiosynthesisHeparan Sulfate ProteoglycanHeparitin SulfateIndividualInjuryInvadedLasersLateralLeadLesionLifeLigandsMediatingModelingMolecularMonitorMotorMotor NeuronsMovementMuscleN-terminalNatural regenerationNerveNerve FibersNerve RegenerationNeurogliaNeuronsPathway interactionsPatientsPeripheral Nervous SystemPeripheral Nervous System DiseasesPhenotypePlayProcessProductionProteinsRecovery of FunctionRegenerative responseResearchRoleSchwann CellsScienceSignal PathwaySignal TransductionSiteSpecificityStagingSurfaceSurveysSynapsesSystemTestingTherapeuticTimeWorkZebrafishaxon growthaxon regenerationcell typeglycosyltransferasehealingin vivoin vivo regenerationinjuredinsightisletlive cell imagingmigrationmutantnerve supplynerve transectionneurodevelopmentnovelperipheral nerve regenerationpreferencepreventreceptorresearch studyresponse to injury
中文摘要
外周神经系统保留了显著的轴突再生能力。作为回应
英文摘要
The peripheral nervous system has retained a remarkable capacity for axonal regeneration. In response to
injury, well-characterized neuron intrinsic signaling pathways mount a regenerative response that eventually
leads to spouting of axonal growth cones. Promoted by well-defined growth factors, growth cones extend along
denervated Schwann cells that they utilize as a general regeneration pathway, yet at branch points individual
regenerating axons have to select the correct path towards their original targets. Although accurate
regeneration of axons to their original targets is critical for the functional recovery, the cellular and molecular
mechanisms by which regenerating axons select their original targets are not well understood.
We recently established an in vivo system to monitor and quantify target selective re-innervation in live
intact animals. Using this system we discovered that following transection of the dorsal and ventral motor nerve
branch, regenerating zebrafish motor axons exhibit a strong preference for their original muscle territory,
providing compelling evidence for the existence of molecular mechanisms for target-selective regeneration. To
identify the genes underlying this process we surveyed mutants in genes with known roles in neural
development. We identified four genes that do not promote axonal regrowth per se, but rather provide target
selectivity to regenerating axons. The experiments in this proposal build upon the findings that in mutants for
the robo2 guidance receptor and for the exostosin like 3 (extl3) glycosyltranferase motor axons develop normal
but regenerating dorsal nerve axons frequently select incorrect, ectopic trajectories, invading lateral and ventral
territories. While both genes play well-defined roles in neural development, their function in regeneration is not
understood. The experiments in this proposal will define the mechanisms by which these two genes promote
target selective regeneration. In Aim 1 we will determine the molecular mechanisms through which robo2
functions in regeneration, e.g. as an axonal Slit receptor, or alternatively as Schwann cell receptor. In Aim 2 we
will determine the cellular mechanisms by which robo2 guides dorsal nerve regeneration, e.g. by correcting
pathfinding mistakes at the choice point, and/or by directing pioneering axons towards their original path,
thereby providing a regeneration pathways for follower axons. Finally, in Aim 3 we will determine whether
exostosin like 3 (extl3) guides regenerating axons through its role in heparan sulfate production or via its
unique surface receptor domain. Combined, the proposed studies will make significant contributions to the
fundamental science of how transected axons return to their original targets. This will results in a better
understanding of peripheral nerve regeneration across the board and will help to address the urgent
therapeutic needs for patients suffering from peripheral neuropathies caused by diabetes, injury, and
autoimmune disorders.
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会议论文
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批准号:10373093
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资助金额:$37.28万
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依托单位:
Graduate Training in Developmental Biology
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批准号:8854902
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资助金额:$32.76万
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财政年份:2015
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Graduate Training in Developmental Biology
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批准号:10640841
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资助金额:$36.62万
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The role of pregnancy associated plasma protein-a in habituation learning
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批准号:8619242
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Molecular identification of genes critical for vertebrate startle modulation
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批准号:8678297
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Genetic analysis of axonal regeneration
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批准号:9301543
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Genetic analysis of axonal regeneration
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Genetic analysis of axonal regeneration
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Cellular and molecular analysis of spontaneous optic nerve regeneration
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资助金额:$54.14万
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依托单位:
The role of pregnancy associated plasma protein-a in habituation learning
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资助金额:$8.0万
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财政年份:2014
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负责人:Michael Granato
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依托单位:
Cellular and molecular analysis of spontaneous optic nerve regeneration
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资助金额:$52.51万
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Genetic analysis of simple learning behaviors
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依托单位:
Genetic analysis of simple learning behaviors
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批准号:7939118
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依托单位:
Genetic analysis of simple learning behaviors
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Axonal degeneration and regeneration in a Zebrafish model of acute nerve injury
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依托单位:
海外基金