Polarized Initiation of Varicosity Formation in Central Neuron Mechanosensation
Polarized Initiation of Varicosity Formation in Central Neuron Mechanosensation
批准号:
9177341
负责人:
CHEN GU
金额:
$34.83万
依托单位:
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:
2016-06-15 至 2020-03-31
关键词:
Action PotentialsAffectAlzheimer&aposs DiseaseAxonBindingBinding ProteinsBiochemicalBiological AssayBrainBrain DiseasesBrain regionCalmodulinCharacteristicsChemicalsChronicChronic DiseaseCoculture TechniquesDendritesDevelopmentDiagnosisDiffuse Axonal InjuryDiseaseElectrophysiology (science)Fluorescence Resonance Energy TransferGlaucomaHealthHippocampus (Brain)ImageInflammationIon ChannelKnockout MiceLightLiquid substanceMechanical StressMechanicsMediatingMembraneMicrotubule-Associated ProteinsMicrotubulesModelingMultiple SclerosisMyelinNerve DegenerationNeuronsOutputParkinson DiseasePatternPhysiologicalProcessProtein BiochemistryProteinsRanvier&aposs NodesRecoveryRegulationResearchRoleSignal TransductionSiteSmall Interfering RNAStagingStressStretchingStructureSwellingSynapsesSynaptic TransmissionTestingTraumatic Brain InjuryVaricosityaxon injurybasedisease-causing mutationinsightinterdisciplinary approachknock-downlive cell imagingmild traumatic brain injurymouse modelnerve injuryneuronal cell bodyneurotransmissionnovelpatch clamppolarized cellpolypeptidepresynapticreceptorresponsetool
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
Little is known about the role of micromechanical stress in regulating neuronal morphological and functional
polarity. Diffuse axonal injury caused by mechanical impact displays characteristic axonal varicosities (swelling
or beading), which are a prominent feature of traumatic brain injury (TBI). Abundant axonal varicosities are
also a key sign for irreversible neurodegeneration in Alzheimer's and Parkinson's diseases, and multiple
sclerosis. Under physiological conditions, a lower level of axonal varicosities can be observed in the brain.
Although axonal varicosities profoundly affect action potential propagation and synaptic transmission, how they
are specifically induced in axons by mechanical stress and regulated in health and disease remains a mystery.
Our preliminary studies have led to several novel findings to shed light on this important question. We found
that mechanical stress induces varicosity formation in unmyelinated axons, but not in dendrites or myelinated
axons of central neurons. This process is unexpectedly rapid and reversible, where a transient receptor
potential (TRP) channel acts as the major mechanosensitive (MS) ion channel. We further identified a novel
binding protein of this channel, which regulates microtubule (MT) disassembly in response to Ca2+ influx.
Moreover, we observed the rapid development of axonal varicosities in the brain of a mouse model of mild TBI.
Based on our preliminary results, we propose an original hypothesis that micromechanical stress
preferentially induces axonal varicosities in central neurons, and this process is regulated by axonal
intrinsic and extrinsic mechanisms. To test this hypothesis, we will use a multidisciplinary approach
including novel microbiomechanical assays, protein biochemistry, electrophysiological recording, state-of-the-
art imaging, myelin coculture, knockout mice and a mild TBI mouse model. We will determine (Aim 1) whether
targeting and activity of MS ion channels regulate polarized mechanosensation in central neurons, (Aim 2) how
MT disassembly is induced by intra-axonal Ca2+ increase and in turn leads to varicosity formation, and (Aim 3)
whether the pattern of axonal varicosity formation in the mild TBI mouse model is regulated by myelin, the MS
channel and its binding protein.
This project represents an underexplored research field with many open questions. This research is significant
because it will provide novel mechanistic insights into a new form of central neuron polarity, polarized
mechanosensation.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Axonal Varicosity Dynamics in Central Neuron Mechanosensation and Injury
-
批准号:10905596
-
项目类别:
-
资助金额:$5.7万
-
财政年份:2023
-
负责人:CHEN GU
-
依托单位:
Axonal Varicosity Dynamics in Central Neuron Mechanosensation and Injury
-
批准号:10599871
-
项目类别:
-
资助金额:$36.48万
-
财政年份:2016
-
负责人:CHEN GU
-
依托单位:
Axonal Varicosity Dynamics in Central Neuron Mechanosensation and Injury
-
批准号:10362748
-
项目类别:
-
资助金额:$36.38万
-
财政年份:2016
-
负责人:CHEN GU
-
依托单位:
Axonal Varicosity Dynamics in Central Neuron Mechanosensation and Injury
-
批准号:10211722
-
项目类别:
-
资助金额:$38.23万
-
财政年份:2016
-
负责人:CHEN GU
-
依托单位:
Mechanism and function of Kv channel targeting
-
批准号:8230710
-
项目类别:
-
资助金额:$28.94万
-
财政年份:2009
-
负责人:CHEN GU
-
依托单位:
Mechanism and function of Kv channel targeting
-
批准号:8022827
-
项目类别:
-
资助金额:$28.94万
-
财政年份:2009
-
负责人:CHEN GU
-
依托单位:
Mechanism and function of Kv channel targeting
-
批准号:7652619
-
项目类别:
-
资助金额:$29.53万
-
财政年份:2009
-
负责人:CHEN GU
-
依托单位:
Mechanism and function of Kv channel targeting
-
批准号:8423350
-
项目类别:
-
资助金额:$27.93万
-
财政年份:2009
-
负责人:CHEN GU
-
依托单位:
海外基金