Dynamic regulation of axonal trafficking and surface distribution of Nav1.7 in sensory neurons
感觉神经元轴突运输和 Nav1.7 表面分布的动态调节
基本信息
- 批准号:10012510
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AGFG1 geneAction PotentialsAfferent NeuronsAftercareAnimal ModelAnkyrinsApplications GrantsAxonBindingBiogenesisCalciumCalcium ChannelCell membraneCentral Nervous System DiseasesCytoskeletonDepositionDevelopmentDiabetes MellitusDiabetic NeuralgiaDiseaseDistalErythromelalgiaFiberGleanGoalsHumanInflammationInflammation MediatorsInheritedKinesinKnowledgeLabelLengthLinkMedicalMembraneMethodologyMitogen-Activated Protein KinasesMolecularMonomeric GTP-Binding ProteinsMotorMultiple TraumaNeuronsNeuropathyNociceptorsOpioidOutcomePainPain DisorderPain managementPaperPatientsPeripheralPhosphorylationPlayProteinsPublicationsRecyclingRegulationRiskRoleSensorySodium ChannelSorting - Cell MovementSpecificitySpeedSurfaceTraumatic Nerve InjuryTraumatic NeuromaVesicleVeteransWorkaddictionchannel blockerschronic paineffective therapyexperimental studygabapentinimprovedin vivoinhibitor/antagonistknock-downlimb amputationnanoclusterneuronal cell bodyneurotransmitter releasenovelnovel strategiespregabalinpresynapticprotein transportreal-time imagesside effecttemporal measurementtherapeutic targettraffickingvesicle transportvoltage
项目摘要
Chronic pain is common among Veterans and remains an unmet medical need. Voltage-gated sodium
channels (NaVs) that are expressed preferentially in primary afferents play a critical role in human pain
disorders, and present opportune targets for the development of novel pain treatments that carry minimal CNS
side effects and addictive potential. NaV1.7 is a peripheral threshold channel that regulates action potential
firing and neurotransmitter release. Our work for the past 15 years has linked NaV1.7 to human pain disorders,
e.g., inherited erythromelalgia, small fiber neuropathy, painful diabetic neuropathy, and validated NaV 1.7 as a
highly attractive target for the treatment of pain. Although considerable progress has been made in the
development of novel NaV1.7 blockers for the treatment of pain, much work is needed to improve their
specificity and efficacy. Similarly, while existing NaV blockers can provide symptomatic relief in patients, their
utility is limited due to non-specificity and significant CNS side effects.
Gabapentinoids, the current first line treatment for chronic pain, inhibit trafficking of presynaptic voltage-gated
calcium channel to the plasma membrane or disrupt Rab11-dependent recycling, thus reducing calcium
currents and transmitter release. By analogy to gabapentinoids' mode of action for the treatment of pain, and
recent focus on trafficking proteins as therapeutic targets in CNS disorder, targeting trafficking machinery of
Nav1.7 might represent a novel approach to pain treatment. However, little is known about molecules and
mechanisms that control sodium channel trafficking and surface distribution along the length of sensory
axons—a target of opportunity that we explore in this proposal.
In this proposal, we aim to elucidate molecular mechanisms that control trafficking of NaV1.7 and their
distribution in the axonal plasma membrane of sensory neurons, in an effort to identify potential new targets for
the treatment of chronic pain. Specifically, we will build upon a powerful new platform that we developed, that
enables real-time imaging of single sodium channels within living sensory neurons at a distance from the soma
with unprecedented spatial- and temporal-resolution.
Knowledge gleaned from these studies will provide unprecedented clarity about mechanisms that regulate sub-
cellular distribution of sodium channels in sensory neurons, particularly along the length of axons, in normal
and disease states. These studies, in turn, will enable discovery of new targets for treatment of chronic pain.
Our ultimate goal is to develop safer and more effective treatments without addictive potential and other
serious side effects.
慢性疼痛在退伍军人中很常见,仍然是一个未满足的医疗需求。电压门控钠
在初级传入神经中优先表达的神经通道(NaVs)在人类疼痛中起着关键作用
疾病,并为开发携带最小CNS的新型疼痛治疗提供了合适的靶点
副作用和上瘾的可能性NaV1.7是调节动作电位的外周阈值通道
放电和神经递质释放。我们在过去15年的工作中将Nav1.7与人类疼痛障碍联系起来,
例如,在一个实施例中,遗传性红斑性肢痛症、小纤维神经病、疼痛性糖尿病神经病,并验证了NaV 1.7作为一种
治疗疼痛的极具吸引力的靶点。虽然在这方面取得了相当大的进展,
尽管开发了用于治疗疼痛的新型NaV1.7阻滞剂,但仍需要大量工作来改善其
特异性和有效性。同样,虽然现有的NaV阻滞剂可以缓解患者的症状,但其
由于非特异性和显著的CNS副作用,其应用受到限制。
加巴喷丁类化合物是目前治疗慢性疼痛的一线药物,可抑制突触前电压门控神经元的运输,
钙通道到质膜或破坏Rab 11依赖的再循环,从而减少钙
电流和变送器释放。通过类比加巴喷丁类化合物用于治疗疼痛的作用模式,
最近的焦点是将运输蛋白质作为CNS疾病的治疗靶点,靶向运输机制,
Nav1.7可能代表了一种新的疼痛治疗方法。然而,人们对分子和
控制钠通道运输和表面分布沿着感觉神经元长度的机制
轴突-我们在这个提议中探索的一个机会目标。
在这项提议中,我们的目标是阐明控制NaV1.7运输的分子机制及其在细胞内的表达。
分布在轴突质膜的感觉神经元,在努力确定潜在的新的目标,
慢性疼痛的治疗具体来说,我们将建立在我们开发的强大的新平台上,
能够对离索马一定距离的活体感觉神经元内的单个钠通道进行实时成像
前所未有的空间和时间分辨率。
从这些研究中收集到的知识将为调节亚健康的机制提供前所未有的清晰度。
正常人感觉神经元中钠通道的细胞分布,特别是沿着轴突的长度,
和疾病状态。反过来,这些研究将有助于发现治疗慢性疼痛的新靶点。
我们的最终目标是开发更安全,更有效的治疗方法,而不会上瘾,
严重的副作用
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Sulayman D Dib-Hajj其他文献
Sulayman D Dib-Hajj的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Sulayman D Dib-Hajj', 18)}}的其他基金
Sodium Channel Nav1.6 in Chemotherapy-Induced Pain
钠通道 Nav1.6 在化疗引起的疼痛中的作用
- 批准号:
10311616 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Sodium Channel Nav1.6 in Chemotherapy-Induced Pain
钠通道 Nav1.6 在化疗引起的疼痛中的作用
- 批准号:
10507771 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Discovery and/or Validation of Pharmacodynamic Markers
药效标记物的发现和/或验证
- 批准号:
10398392 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Dynamic regulation of axonal trafficking and surface distribution of Nav1.7 in sensory neurons
感觉神经元轴突运输和 Nav1.7 表面分布的动态调节
- 批准号:
10618775 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Dynamic regulation of axonal trafficking and surface distribution of Nav1.7 in sensory neurons
感觉神经元轴突运输和 Nav1.7 表面分布的动态调节
- 批准号:
10293536 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Sodium Channel Nav1.6 in Chemotherapy-Induced Pain
钠通道 Nav1.6 在化疗引起的疼痛中的作用
- 批准号:
10700086 - 财政年份:2021
- 资助金额:
-- - 项目类别:
相似海外基金
Kilohertz volumetric imaging of neuronal action potentials in awake behaving mice
清醒行为小鼠神经元动作电位的千赫兹体积成像
- 批准号:
10515267 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Signal processing in horizontal cells of the mammalian retina – coding of visual information by calcium and sodium action potentials
哺乳动物视网膜水平细胞的信号处理 â 通过钙和钠动作电位编码视觉信息
- 批准号:
422915148 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Research Grants
CAREER: Resolving action potentials and high-density neural signals from the surface of the brain
职业:解析来自大脑表面的动作电位和高密度神经信号
- 批准号:
1752274 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Continuing Grant
Development of Nanosheet-Based Wireless Probes for Multi-Simultaneous Monitoring of Action Potentials and Neurotransmitters
开发基于纳米片的无线探针,用于同时监测动作电位和神经递质
- 批准号:
18H03539 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (B)
Population Imaging of Action Potentials by Novel Two-Photon Microscopes and Genetically Encoded Voltage Indicators
通过新型双光子显微镜和基因编码电压指示器对动作电位进行群体成像
- 批准号:
9588470 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Enhanced quantitative imaging of compound action potentials in multi-fascicular peripheral nerve with fast neural Electrical Impedance Tomography enabled by 3D multi-plane softening bioelectronics
通过 3D 多平面软化生物电子学实现快速神经电阻抗断层扫描,增强多束周围神经复合动作电位的定量成像
- 批准号:
10009724 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Enhanced quantitative imaging of compound action potentials in multi-fascicular peripheral nerve with fast neural Electrical Impedance Tomography enabled by 3D multi-plane softening bioelectronics
通过 3D 多平面软化生物电子学实现快速神经电阻抗断层扫描,增强多束周围神经复合动作电位的定量成像
- 批准号:
10467225 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Fast high-resolution deep photoacoustic tomography of action potentials in brains
大脑动作电位的快速高分辨率深度光声断层扫描
- 批准号:
9423398 - 财政年份:2017
- 资助金额:
-- - 项目类别:
NeuroGrid: a scalable system for large-scale recording of action potentials from the brain surface
NeuroGrid:用于大规模记录大脑表面动作电位的可扩展系统
- 批准号:
9357409 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Noval regulatory mechanisms of axonal action potentials
轴突动作电位的新调节机制
- 批准号:
16K07006 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)