Role of Nociceptor Primary Cilia in Inflammatory and Neuropathic Pain
伤害感受器初级纤毛在炎症和神经性疼痛中的作用
基本信息
- 批准号:10575524
- 负责人:
- 金额:$ 39.05万
- 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:2022-09-23 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdultAfferent NeuronsAnimalsAxonBindingBrainCarrier ProteinsCell surfaceCellsCerebellumCerebral cortexCiliaComplexCorpus striatum structureCre driverDataDependenceDevelopmentDrosophila genusElectrophysiology (science)Embryonic DevelopmentEnterobacteria phage P1 Cre recombinaseErinaceidaeFamilyGenesGenetic TranscriptionHairHippocampal FormationHippocampus (Brain)HyperalgesiaInflammatoryIntrathecal InjectionsKnock-inLigandsMammalsMediatingModelingModificationMusMutant Strains MiceNervous system structureNeuronsNociceptionNociceptorsOrganellesPainPain ThresholdPain managementPathway interactionsPharmacologyPhysiologicalPlayProcessProteinsRattusResearchResearch ProposalsRodent ModelRoleSignal TransductionSignal Transduction PathwaySmall Interfering RNASpinal CordSpinal GangliaStructureSubstantia nigra structureSurfaceSystemTestingTranslationsWorkanterograde transportbasebody systemchronic painconditional knockoutdruggable targetgain of functionhedgehog signal transductioninflammatory paininformation processinginnovationknock-downloss of functionmouse modelmutantneuronal cell bodynigrostriatal systemnovel therapeuticspain signalpainful neuropathyreceptorresponseretrograde transportsmoothened signaling pathwaytool
项目摘要
Primary cilia are short hair-like structures protruding from the surface of almost all cells in the
vertebrate body. In the nervous system, cilia are critical for both the development and the function
of neurons, including in spinal cord, cerebral cortex, hippocampus, the nigrostriatal system, and
the cerebellum. Sensory neurons of the dorsal root ganglia (DRG) elaborate a single primary
cilium at their soma shortly after they are born in embryogenesis and migrate into the DRG.
However, nothing is known about potential functions that primary cilia may have in the function of
mature DRG neurons. Recent work in the fruit fly and in the rat have shown a role for Hedgehog
signaling in nociceptive sensitization. In mammals, the Hedgehog pathway demonstrates a
dependence upon primary cilia for signal transduction. This research proposal seeks to test the
hypothesis that primary cilia expressed by nociceptive neurons of the DRG modulate nociceptive
signals arriving from the periphery and thereby modulate nociceptive signaling under normal
physiological conditions and during pathophysiological states. In Specific Aim 1 we shall
investigate the importance of primary cilia in pain thresholds and in models of inflammatory and
neuropathic pain in both rat and mouse models. In Specific Aim 2 we shall test the role of
Hedghog signalling in the modulation of threshold, inflammatory, and chronic pain states in PIPN,
and we shall examine the dependence of Hedgehog signalling upon primary cilia of DRG neurons.
Aim 2 examines the hypothesis that Hedgehog signaling mediates hyperalgesia in both
inflammatory and PIPN pain states. In the rat, siRNA targeting primary cilium-specific intraflagellar
transport (IFT) genes will be administered to lumbar DRGs through intrathecal injection. siRNA-
mediated knockdown of these genes specifically leads to a loss of the primary ciliary function. In
the mouse, knock-in lines expressing a Cre recombinase integrated into the NaV1.8 locus shall
be used as a tool to specifically eliminate the IFT gene Ift88 in nociceptive neurons.
Pharmacological and siRNA-based modification of PIPN and Hedgehog signaling in both
knockdown and wildtype rats, as well as loss-of-function and gain-of-function mouse mutants in
primary cilia and in Hedgehog signaling, shall be employed. The significance of this project is that
we shall elucidate Hedgehog as a new signal transduction pathway for the modification of chronic
pain states, and also the locus at which it acts, the primary cilium. Both the cilium and the
Hedgehog pathway offer multiple druggable targets that may prove amenable for translation into
novel therapeutics for pain therapy.
初级纤毛是毛发状的短结构,从几乎所有细胞的表面突出
项目成果
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