Lymphocyte Antigen 6 (Ly6) Proteins: New Players in Chronic Pain
淋巴细胞抗原 6 (Ly6) 蛋白:慢性疼痛的新参与者
基本信息
- 批准号:10784019
- 负责人:
- 金额:$ 23.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-25 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:Action PotentialsAffectAfferent NeuronsAnalgesicsBehaviorBehavioralBindingBiochemicalBiological AssayCell CommunicationCell MaturationCell ProliferationCellsClosure by clampDataDissociationDown-RegulationElectrophysiology (science)EvaluationExtracellular ProteinFingersFluorescence-Activated Cell SortingGene FamilyGenerationsGenesGeneticGenus LynxGlycoproteinsGlycosylphosphatidylinositolsGoalsHumanImmuneIn Situ HybridizationInjuryIntrathecal InjectionsInvadedKnock-outKnockout MiceLY6E geneLeadLearningLigationLinkLipidsLymphocyte antigenMacrophageMacrophage ActivationMalignant NeoplasmsMeasuresMembraneModelingMolecularMusNerve FibersNeuronsNeuropathyNicotinic ReceptorsNociceptionOrthologous GenePainPain ThresholdPathologicPatientsPatternPeptidesPhysiologicalPlasmidsPlayPopulationProductionProtein FamilyProteinsRattusRegulationReportingRodentRoleShaker potassium channelSignal TransductionSmall Interfering RNASnake VenomsSodiumSodium ChannelSpecificitySpinal CordSpinal GangliaStimulusSumoylation PathwaySurfaceSyndromeTechniquesTestingTimeToxinTransfectionUp-RegulationValidationafferent nervebiophysical propertiescancer typecell motilitychronic neuropathic painchronic paincollapsin response mediator protein-2confocal imagingcytokinedesignextracellulargain of function mutationin vivomechanical allodyniamolecular sequence databasenerve injuryneuronal excitabilityneurotransmissionneurotransmitter releasenoveloverexpressionpain behaviorpain reliefpain signalpainful neuropathypatch clamppostsynapticprotein protein interactionresponsesensory systemspared nervetraffickingtranscriptome sequencingubiquitin-protein ligasevoltage
项目摘要
PROJECT SUMMARY
Chronic pain is a pathological state where sensory neurons become hyperexcitable leading to nociceptive
neurotransmission in the absence of a painful stimulus. Genetic and functional studies have established the
voltage-gated sodium channel NaV1.7 as a major contributor to human pain signaling. Although the regulation of
NaV1.7 is poorly understood, it is thought to involve mechanisms related to surface trafficking and regulation via
protein-protein interactions. For instance, upregulation of SUMOylation of cytosolic collapsin response mediator
protein 2 (CRMP2) and VGSC β-subunits, and downregulation of Nedd4-2 (a cytosolic E3 ubiquitin ligase) in a
model of spared nerve injury induced chronic pain result in functional upregulation of NaV1.7 channels. My
studies have identified lymphocyte antigen 6 (Ly6) proteins as a novel class of NaV1.7 channel modulators.
Ly6 proteins are extracellular glycoproteins that are a hallmark of different types of cancer and have a role in
cell proliferation, cell migration, cell–cell interactions, immune cell maturation, macrophage activation, and
cytokine production. Ly6 proteins show structural resemblance to the three-fingered snake venom toxins
that are known to modulate nicotinic acetylcholine receptors and voltage-gated sodium channels. Of
these group of proteins, Ly6e and Lynx1 are common between humans and rodents. RNA-sequencing
databases showed that both Ly6e and Lyn1 expression increases in different populations of dorsal root ganglia
(DRG) neurons after nerve injury. Moreover, my preliminary findings show that: (i) there are higher Ly6e signal
levels in DRGs after spared nerve injury (SNI); (ii) overexpression of Ly6e is associated with increased sodium
currents in DRGs, and NaV1.7 currents in HEK cells; and (iii) intrathecal injection of Ly6e plasmid induces pain-
like behaviors in naïve rats. These data led me to hypothesize that: (i) modulation of NaV1.7 channels by Ly6e
and Lynx1 may lead to altered expression and activity of these channels during chronic pain, and that (ii)
interfering with NaV1.7-Ly6e/Lynx1 interactions may relieve pain. Thus, the goals of this proposal are to
investigate the role of Ly6 proteins (i) in sensory neurons and (ii) as molecular determinants of the altered
functional activity of NaV1.7 channels in pain states. My Specific Aims are: (1) Investigate the physiological
function(s) of Ly6e and Lynx1 in primary sensory neurons from rodents with and without nerve injury; (2) Identify
and characterize Ly6e and Lynx1 as modulators of NaV1.7 channels in rodent and human dorsal root ganglia
neurons; and (3) Identify specific interaction domain(s) in NaV1.7, Ly6e and Lynx1 and validation of in vivo target
engagement. These studies are anticipated to advance our understanding of the role of Ly6e and Lynx1 in the
sensory system, and their role as modulators of a key pain-associated voltage-gated sodium channel, NaV1.7.
项目总结
项目成果
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