Axonal Transport and Local Translation in Neuropathic Pain

神经性疼痛中的轴突运输和局部翻译

• 批准号: 7492307
• 负责人: Dianna E. Willis
• 金额: $ 8.69万
• 依托单位: ALFRED I. DU PONT HOSP FOR CHILDREN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-04 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7492307
• 关键词: Address; Adult; Afferent Neurons; Animal Model; Axon; Axonal Transport; Biological; CALCA gene; Calcitonin Gene-Related Peptide; Cells; Chimeric Proteins; Chronic; Complex; Constriction procedure; Dendrites; Distal; Elements; Environment; Epitopes; Exhibits; Goals; Golgi Apparatus; Growth; Growth Cones; In Vitro; Infection; Inflammation; Injury; Ion Channel; Ion Channel Protein; Ions; Localized; Location; Membrane; Membrane Proteins; Messenger RNA; Methods; Modeling; Molecular; Natural regeneration; Nerve; Nerve Growth Factor 1; Nerve Growth Factor Pathway; Neurons; Neuropeptides; Pain; Peripheral; Peripheral Nerves; Play; Population; Process; Protein Biosynthesis; Proteins; Proteomics; RNA; Rattus; Regulation; Reporter; Research Personnel; Role; Rough endoplasmic reticulum; S100A12 gene; Screening procedure; Sensory; Signal Transduction; Spinal Cord; Stimulus; Structure; Substance P; Synaptic plasticity; Thinking; Transcript; Transgenic Mice; Translations; Trauma; Work; cDNA Arrays; chronic constriction injury; chronic pain; experience; human S100A12 protein; in vivo; insight; neuropeptide Y; neurotrophic factor; painful neuropathy; programs; response; trafficking; transmission process

DESCRIPTION (provided by applicant): Localized protein synthesis provides a means for the distal processes of the neuron to rapidly and autonomously respond to its environment. Although best characterized in the dendritic compartment, work over the past 5 years has proven that axons are capable of locally generating new proteins. In dendrites, activity-dependent local protein synthesis plays a role in synaptic plasticity. There is also evidence for activity-dependent protein synthesis in axons. Given the complex population of proteins synthesized in axons, it is likely that axonally synthesized proteins also play a role in the function of mature axons. The central hypothesis of this proposal is that changes in local protein synthesis in sensory axons alter the neuron's capacity for propagating noxious stimuli. The objective of this proposal is to understand how axonal transport and local protein synthesis contribute to hyperexcitability exhibited by damaged neurons leading to neuropathic pain states. We will use in vitro and in vivo methods to determine if the transport and sub-axonal localization of ion channel and neurotpeptide mRNAs are altered in neuropathic pain, and whether locally synthesized ion channels are functionally inserted into axoplasmic membranes and if this translation and trafficking are altered by neuropathic pain-associated stimuli. We will utilized chimeric mRNA reporter constructs to address axonal localization of these transcripts, both in cultured primary sensory neurons and in transgenic mice. GFP-tagged fusion proteins of locally synthesized ion channel proteins will be used to determine the functional relevance of axonally synthesized ion channels, with the ultimate goal of understanding how axonal trafficking and local synthesis of these proteins contributes to neuropathic pain. Neuropathic pain, the chronic pain experienced following injury, infection, or inflammation of peripheral nerves, sharply contrasts with normal pain, both is the molecular mechanisms which cause it and in their responses to conventional pain treatments. Current animal models of nerve trauma have provided some insights into the neuronal changes that occur in response to peripheral nerve damage - revealing a remarkable degree of plasticity in both the sensory neurons and spinal cord. Understanding how axonal transport and local protein synthesis contribute to increased hyperexcitability of these damaged sensory neurons may point to alternative methods of treating pathological pain states.

描述(由申请人提供)： 局部蛋白质合成为神经元的远端突起提供了一种快速和自主地对环境做出反应的手段。尽管最好的特征是在树突室，但过去5年的研究证明，轴突能够在局部产生新的蛋白质。在树突中，依赖活性的局部蛋白质合成在突触可塑性中发挥作用。也有证据表明，轴突中存在活性依赖的蛋白质合成。考虑到在轴突中合成的蛋白质的复杂群体，轴突合成的蛋白质很可能也在成熟轴突的功能中发挥作用。这一建议的中心假设是感觉轴突中局部蛋白质合成的变化改变了神经元传播伤害性刺激的能力。这项建议的目的是了解轴突运输和局部蛋白质合成如何促进受损神经元表现出的过度兴奋性，从而导致神经病理性疼痛状态。我们将使用体外和体内方法来确定神经病理性疼痛中离子通道和神经肽mRNAs的运输和轴突下定位是否改变，局部合成的离子通道是否功能性地插入轴浆膜，以及这种翻译和运输是否被神经病理性疼痛相关刺激改变。我们将利用嵌合的mRNA报告结构来解决这些转录物在培养的初级感觉神经元和转基因小鼠中的轴突定位。GFP标记的局部合成的离子通道蛋白的融合蛋白将用于确定轴突合成的离子通道的功能相关性，最终目的是了解这些蛋白的轴突运输和局部合成如何与神经病理性疼痛有关。神经病理性疼痛，即周围神经损伤、感染或炎症后所经历的慢性疼痛，与正常疼痛形成鲜明对比，两者都是引起它的分子机制，以及它们对传统疼痛治疗的反应。目前的神经创伤动物模型为周围神经损伤后神经元的变化提供了一些见解--揭示了感觉神经元和脊髓都具有显著的可塑性。了解轴突运输和局部蛋白质合成如何导致这些受损感觉神经元的超兴奋性增加，可能会为治疗病理性疼痛状态的替代方法指明方向。

项目成果

Selective repression of gene expression in neuropathic pain by the neuron-restrictive silencing factor/repressor element-1 silencing transcription (NRSF/REST).

• DOI: 10.1016/j.neulet.2015.12.003
• 发表时间: 2016-06-20
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Willis DE;Wang M;Brown E;Fones L;Cave JW
• 通讯作者: Cave JW

Probucol is anti-hyperalgesic in a mouse peripheral nerve injury model of neuropathic pain.

• DOI: 10.1016/j.ynpai.2023.100141
• 发表时间: 2023-08
• 期刊: Neurobiology of pain (Cambridge, Mass.)
• 作者: Joyce, Rebecca L.;Tibbs, Gareth R.;Warren, J. David;Costa, Christopher J.;Aromolaran, Kelly;Sanford, R. Lea;Andersen, Olaf S.;Li, Zhucui;Zhang, Guoan;Willis, Dianna E.;Goldstein, Peter A.
• 通讯作者: Goldstein, Peter A.

Nicotinamide Riboside Improves Enteric Neuropathy in Streptozocin-Induced Diabetic Rats Through Myenteric Plexus Neuroprotection.

烟酰胺核苷通过肌间丛神经保护改善链佐星诱导的糖尿病大鼠的肠神经病变。

• DOI: 10.1007/s10620-023-07913-5
• 发表时间: 2023
• 期刊: Digestive diseases and sciences
• 影响因子: 3.1
• 作者: Costa,ChristopherJ;Cohen,MelanieW;Goldberg,DavidC;Mellado,Wilfredo;Willis,DiannaE
• 通讯作者: Willis,DiannaE