Molecular Mechanism of Brain Regulation of Chronic Pain
大脑调节慢性疼痛的分子机制
基本信息
- 批准号:10580604
- 负责人:
- 金额:$ 23.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AMPA ReceptorsASIC channelAblationAcidsAdverse effectsAffectAffectiveAnimalsAnteriorAreaBehavior assessmentBehavioral AssayBindingBiochemicalBiochemistryBiologicalBrainBrain regionCellsCellular biologyCentral Nervous SystemChemicalsChinaChineseClinicalCollaborationsDevelopmentDiffusionElectrophysiology (science)EthylmaleimideFiberGenesGoalsHyperalgesiaHypersensitivityIn SituInflammationInflammatoryInjuryIon ChannelIonsLaboratoriesLateralLeadLong-Term PotentiationMaintenanceMechanical StimulationMedicalMembraneMolecularMolecular and Cellular BiologyMotivationN-ethylmaleimide-sensitive proteinNamesNeuronsNociceptionNon-Steroidal Anti-Inflammatory AgentsOpioidPainPain managementPathway interactionsPeripheralPeripheral Nervous SystemPersonsPharmaceutical PreparationsPhasePlayPopulationPostsynaptic MembraneProsencephalonProtein IsoformsRecyclingRegulationResearchRoleSensoryStimulusStructureSurfaceSynapsesSynaptic plasticityTechnical ExpertiseTechniquesTestingabuse liabilitybehavioral studycentral painchronic painchronic pain managementcingulate cortexexcitatory neuronexperienceextracellularimaging approachinflammatory paininhibitorinnovationmechanical allodyniamigrationmouse modelnerve injurynovel therapeuticsoptogeneticspain behaviorpain chronificationpain modelpain perceptionpain processingpain sensationpainful neuropathypharmacologicprotein protein interactionreceptorresponseside effectspared nervesuperresolution imagingtrafficking
项目摘要
PROJECT SUMMARY
Chronic pain is debilitating medical problem that affects millions of people. However, current clinical
therapy relying on opioids and non-steroidal anti-inflammatory drugs has limited efficacy because of severe
adverse effects and abuse potential. To overcome these limitations, more in-depth illustration of the
mechanism that underlies the development and maintenance of chronic pain will be extremely helpful. Pain
perception consists of both peripheral and central components. While the peripheral mechanisms of pain
have been well studied, our current understanding of the central mechanism of pain perception, especially
with respect to chronic pain, remains rather limited. The current project focuses on the mechanism by which
anterior cingulate cortex (ACC) of the brain participates in pain perception. It has been well-established that
synaptic plasticity in ACC represents one of the most critical mechanisms underlying the transition of pain
from acute to chronic. Using mouse models of chronic pain induced by peripheral inflammatory and spared
nerve injury, the research team has obtained strong evidence that acid-sensing ion channel isoform 1a
(ASIC1a) plays a pivotal role in both the development and maintenance of chronic pain. Not only did ACC
neuron specific ablation of ASIC1a gene mitigated inflammatory hyperalgesia and mechanical allodynia, but
in situ pharmacological inhibition of ASIC1a at ACC also quickly reversed the pre-established pain
hypersensitivity. More intriguingly, in situ focal application of an ASIC1a activator at ACC enhanced
sensitivity to peripheral thermal and mechanical stimulation within 10 minutes in the absence of peripheral
inflammation or injury, indicating a crucial role of ACC ASIC1a activity in pain processing. The current
project aims to elucidate the mechanism by which ACC ASIC1a regulates central pain processing at
molecular, cellular and functional levels. The central hypothesis is that in ACC excitatory neurons that
receive persistent nociceptive inputs, ASIC1a, in an ion conduction-independent manner, facilitates
cingulate long-term potentiation through promoting forward trafficking of AMPA receptors. The enhanced
synaptic efficacy in turn leads to altered sensitivity and reactivity of the pain pathways. The two specific aims
are to define molecular underpinnings of ASIC1a regulation of AMPAR trafficking during the course of LTP
induction and expression in ACC excitatory neurons (AIM 1) and illustrate functional relevance of molecular
interactions that control AMPAR trafficking in cingulate LTP and chronic pain (AIM 2). The collaborative
project will combine the unique strengths of the two laboratories in biochemical and cell biological analysis
(US lab) and electrophysiological and behavioral study of plasticity and pain (China lab) to accomplish the
goals. The project will greatly enhance our understanding on mechanism of ASIC1a regulation of synaptic
plasticity, especially as it relates to pain hypersensitivity through enhancing synaptic efficacy at supraspinal
levels, and shed new lights on more effective ways to treat chronic pain with minimal side effects.
项目摘要
慢性疼痛是使人衰弱的医学问题,影响数百万人。目前临床
依赖于阿片类药物和非甾体抗炎药的治疗由于严重的
副作用和滥用的可能性。为了克服这些限制,更深入地说明
研究慢性疼痛的发展和维持机制将非常有帮助。疼痛
知觉由外围和中心两部分组成。虽然疼痛的外围机制
已经得到了很好的研究,我们目前对疼痛感知的中枢机制的理解,特别是
在慢性疼痛方面,仍然相当有限。目前的项目侧重于以下机制:
大脑的前扣带皮层(ACC)参与疼痛感知。众所周知,
ACC中的突触可塑性代表了疼痛转变的最关键机制之一
从急性到慢性采用小鼠外周炎性慢性疼痛模型,
神经损伤,研究小组已经获得了强有力的证据,酸敏感离子通道亚型1a
ASIC1a在慢性疼痛的发展和维持中起着关键作用。不仅ACC
ASIC1a基因的神经元特异性消融减轻了炎性痛觉过敏和机械性异常性疼痛,但
ACC的ASIC1a的原位药理学抑制也迅速逆转了预先建立的疼痛
超敏反应更有趣的是,在ACC原位局灶性应用ASIC1a激活剂,
在没有外周刺激的情况下,10分钟内对外周热和机械刺激的敏感性
炎症或损伤,表明ACC ASIC1a活性在疼痛处理中的关键作用。当前
该项目旨在阐明ACC ASIC1a调节中枢疼痛处理的机制,
分子、细胞和功能水平。核心假设是,在ACC兴奋性神经元中,
接受持续性伤害性输入,ASIC1a,以离子传导独立的方式,促进
通过促进AMPA受体的前向运输来形成扣带长时程增强。增强的
突触功效又导致疼痛通路的敏感性和反应性改变。两个具体目标
目的是确定LTP过程中ASIC1a调节AMPAR运输的分子基础
在ACC兴奋性神经元(AIM 1)中诱导和表达,并说明分子功能相关性
控制扣带LTP和慢性疼痛(AIM 2)中AMPAR运输的相互作用。合作
该项目将联合收割机结合两个实验室在生化和细胞生物学分析方面的独特优势
(US实验室)和可塑性和疼痛的电生理和行为研究(中国实验室),以完成
目标.本项目将极大地加深我们对ASIC1a调控突触的机制的理解,
可塑性,特别是因为它涉及到疼痛超敏反应,通过增强突触的效力,在脊髓上
水平,并揭示了更有效的方法来治疗慢性疼痛,最小的副作用。
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)
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MICHAEL X ZHU其他文献
MICHAEL X ZHU的其他文献
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{{ truncateString('MICHAEL X ZHU', 18)}}的其他基金
Regulatory mechanisms of lysosomal degradation in neurodegenerative disease
神经退行性疾病中溶酶体降解的调节机制
- 批准号:
10354193 - 财政年份:2021
- 资助金额:
$ 23.4万 - 项目类别:
Molecular Mechanism of Brain Regulation of Chronic Pain
大脑调节慢性疼痛的分子机制
- 批准号:
10349433 - 财政年份:2020
- 资助金额:
$ 23.4万 - 项目类别:
The role of two-pore channels in integrative calcium signaling
双孔通道在整合钙信号传导中的作用
- 批准号:
8319479 - 财政年份:2010
- 资助金额:
$ 23.4万 - 项目类别:
The role of two-pore channels in integrative calcium signaling
双孔通道在整合钙信号传导中的作用
- 批准号:
8537939 - 财政年份:2010
- 资助金额:
$ 23.4万 - 项目类别:
The role of two-pore channels in integrative calcium signaling
双孔通道在整合钙信号传导中的作用
- 批准号:
7863955 - 财政年份:2010
- 资助金额:
$ 23.4万 - 项目类别:
The role of two-pore channels in integrative calcium signaling
双孔通道在整合钙信号传导中的作用
- 批准号:
8144875 - 财政年份:2010
- 资助金额:
$ 23.4万 - 项目类别:
Molecular mechanism of regulation of mI(CAT) in intestinal smooth muscle cells
肠平滑肌细胞mI(CAT)调控的分子机制
- 批准号:
8278680 - 财政年份:2009
- 资助金额:
$ 23.4万 - 项目类别:
Molecular mechanism of regulation of mI(CAT) in intestinal smooth muscle cells
肠平滑肌细胞mI(CAT)调控的分子机制
- 批准号:
7762745 - 财政年份:2009
- 资助金额:
$ 23.4万 - 项目类别:
Molecular mechanism of regulation of mI(CAT) in intestinal smooth muscle cells
肠平滑肌细胞mI(CAT)调控的分子机制
- 批准号:
8207618 - 财政年份:2009
- 资助金额:
$ 23.4万 - 项目类别:
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