Harnessing T-junction filtering; bidirectional control of sensory neuron impulse traffic
利用 T 形接头过滤;
基本信息
- 批准号:9419475
- 负责人:
- 金额:$ 47.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-15 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:Absence of pain sensationAction PotentialsAcute PainAfferent NeuronsAnatomyAnimal Disease ModelsAnimalsAxonBehavioralBrain imagingClinicalComplementControl AnimalDataDegenerative polyarthritisDiseaseElectrophysiology (science)EsthesiaFDA approvedFemaleFoundationsFunctional Magnetic Resonance ImagingGangliaGenerationsGoalsIn VitroInflammationInflammatoryInflammatory ArthritisJointsMeasuresMechanoreceptorsMembraneModalityModelingMolecularNeuraxisNeurogenic InflammationNeuronsNeuropathyNeurostimulation procedures of spinal cord tissueNociceptorsOpticsOrganPainPain managementPathway interactionsPeripheralPeripheral NervesPeripheral Nervous SystemPharmacologyPhysiologicalPopulationPreparationProcessProductionPropertyRattusReflex actionRegulationRheumatoid ArthritisRoleSensorySignal TransductionSpinal GangliaSystemTestingTherapeuticTissuesTrainingbehavior testcalmodulin-dependent protein kinase IIchronic painclinical applicationdesigner receptors exclusively activated by designer drugsdorsal columndorsal hornexperimental studyin vivomaleneuronal cell bodyneuroregulationnoveloptogeneticspreferencepreventreceptive fieldsensory systemspinal nerve posterior roottransmission process
项目摘要
Sensory neurons naturally adapt to ongoing stimulation, but harnessing this inherent plasticity for therapeutic
purposes has not been explored. The recent clinical observation that dorsal root ganglion field stimulation (GFS)
blocks pain, provides a clue that an unrecognized process regulates conduction of impulses through the DRG
since exactly the opposite, i.e. production of pain, would be expected. The paradoxical phenomenon of GFS
analgesia indicates that our current understanding of peripheral neuron signal transmission is fundamentally
insufficient, and that a novel, clinically applicable modality of use-dependent neuronal manipulation awaits
discovery. That is the goal of this proposal. Sensory neurons also convey retrograde impulses from the dorsal
horn to peripheral tissues, where they trigger inflammation and tissue damage, for instance in rheumatoid
arthritis. We will therefore explore bidirectional GFS modulation of both afferent and efferent signal transmission
through the DRG. In three Aims, we will test the overall hypothesis that GFS, by triggering action potentials (APs)
in the somata of sensory neurons, reduces the intrinsic excitability of their T-junction, which reduces bidirectional
propagation of APs through the DRG, and can thereby produce analgesia and block neurogenic inflammation.
In Aim 1, we will first develop a rat model in order to lay the groundwork for mechanistic exploration. GFS
analgesia will be tested in the setting of neuropathy, and osteoarthritis. To test GFS blockade of retrograde
impulses, we will identify GFS effects on joint changes in a model of rheumatoid arthritis. For these experiments,
examination will be by behavioral tests and functional magnetic resonance imaging (fMRI) of the brain, examining
both male and female rats. In Aim 2, to identify the exact neuronal targets of GFS, we will test GFS activation of
sensory neuron somata, and determine which DRG neuronal subtypes are modulated by GFS and at which
component (axon vs. soma) this takes place. Aim 3 will employ electrophysiological approaches to directly
measure the effects of GFS on functional properties of DRG neurons, in order to identify the mechanism of GFS
impulse regulation. Additionally, we will explore the role of CaMKII, and we will compare GFS effects between
the various sensory neuron subpopulations.
Together, our proposed experiments will establish a mechanistic foundation for a novel regulatory process that
governs impulse train transmission in the peripheral nervous system. As molecular and electrical
neuromodulatory therapies move forward in the clinical setting, understanding this new regulatory node will have
direct translational utility for harnessing an inherent impulse regulating system and applying it to control sensory
and peripheral inflammatory disorders.
感觉神经元自然适应持续的刺激,但要利用这种固有的可塑性来治疗
目的尚未探讨。最近的临床观察结果是背根神经节刺激(GFS)
阻止疼痛,提供了一个线索,即无法识别的过程调节通过DRG传导冲动
由于恰恰相反,即疼痛的产生。 GFS的悖论现象
镇痛表明我们目前对周围神经元信号传递的理解从根本上是
不足,这是一种新颖的,临床上适用的使用依赖性神经元操作的方式
发现。这就是该提议的目标。感觉神经元还传达了背面的逆行冲动
喇叭到周围组织,它们会触发炎症和组织损伤,例如在类风湿中
关节炎。因此,我们将探索传入和传出信号传递的双向GFS调制
通过DRG。在三个目标中,我们将通过触发动作电位(AP)来检验GFS的总体假设。
在感觉神经元的索马群中,降低了其T结的内在兴奋性,从而降低了双向
AP通过DRG传播,从而产生镇痛并阻止神经源性炎症。
在AIM 1中,我们将首先开发大鼠模型,以奠定机械探索的基础。 GFS
镇痛将在神经病和骨关节炎的情况下进行测试。测试GFS逆行的封锁
冲动,我们将确定GFS对类风湿关节炎模型中关节变化的影响。对于这些实验,
检查将通过大脑的行为测试和功能磁共振成像(fMRI)进行检查
男性和雌性老鼠。在AIM 2中,为了确定GFS的确切神经元靶标,我们将测试GFS激活
感觉神经元somata,并确定哪些DRG神经元亚型由GFS调节
组件(Axon vs. Soma)发生。 AIM 3将采用电生理方法直接
测量GFS对DRG神经元功能特性的影响,以识别GFS的机制
冲动调节。此外,我们将探讨Camkii的作用,并将比较GFS的影响
各种感觉神经元亚群。
我们提出的实验将共同为新的调节过程建立机械基础,
控制周围神经系统中的冲动火车传播。作为分子和电气
神经调节疗法在临床环境中前进,了解这种新调节节点将具有
直接翻译实用程序来利用固有的冲动调节系统并将其应用于控制感官
和周围炎症性疾病。
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)
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Quinn H Hogan其他文献
Quinn H Hogan的其他文献
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{{ truncateString('Quinn H Hogan', 18)}}的其他基金
Primary sensory neuron-targeted block of Cav3.2 for treatment of chronic neuropathic pain
初级感觉神经元靶向的 Cav3.2 阻断治疗慢性神经性疼痛
- 批准号:
10438951 - 财政年份:2021
- 资助金额:
$ 47.1万 - 项目类别:
Primary sensory neuron-targeted block of Cav3.2 for treatment of chronic neuropathic pain
初级感觉神经元靶向的 Cav3.2 阻断治疗慢性神经性疼痛
- 批准号:
10452646 - 财政年份:2021
- 资助金额:
$ 47.1万 - 项目类别:
Harnessing T-junction filtering; bidirectional control of sensory neuron impulse traffic
利用 T 形接头过滤;
- 批准号:
10200908 - 财政年份:2017
- 资助金额:
$ 47.1万 - 项目类别:
Persisting functional CNS changes following peripheral nerve repair
周围神经修复后中枢神经系统功能持续变化
- 批准号:
9031926 - 财政年份:2016
- 资助金额:
$ 47.1万 - 项目类别:
Persisting functional CNS changes following peripheral nerve repair
周围神经修复后中枢神经系统功能持续变化
- 批准号:
9198176 - 财政年份:2016
- 资助金额:
$ 47.1万 - 项目类别:
AAV-encoded analgesic peptide aptamers for chronic pain
AAV编码的镇痛肽适体治疗慢性疼痛
- 批准号:
9079673 - 财政年份:2016
- 资助金额:
$ 47.1万 - 项目类别:
Cannabinoid Signaling in the dPAG: Specific Analgesic and Autonomic Functions
dPAG 中的大麻素信号传导:特定的镇痛和自主功能
- 批准号:
8625117 - 财政年份:2013
- 资助金额:
$ 47.1万 - 项目类别:
Cannabinoid Signaling in the dPAG: Specific Analgesic and Autonomic Functions
dPAG 中的大麻素信号传导:特定的镇痛和自主功能
- 批准号:
8762234 - 财政年份:2013
- 资助金额:
$ 47.1万 - 项目类别:
Cannabinoid Signaling in the dPAG: Specific Analgesic and Autonomic Functions
dPAG 中的大麻素信号传导:特定的镇痛和自主功能
- 批准号:
8966633 - 财政年份:2013
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$ 47.1万 - 项目类别:
DRG engraftment of transduced mesenchymal stem cells to treat neuropathic pain
转导间充质干细胞的 DRG 植入治疗神经性疼痛
- 批准号:
8847814 - 财政年份:2012
- 资助金额:
$ 47.1万 - 项目类别:
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