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:10349433
- 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 biologyChemicalsChinaChineseClinicalDevelopmentDiffusionElectrophysiology (science)EthylmaleimideFiberGenesGoalsHyperalgesiaHypersensitivityIn SituInflammationInflammatoryInjuryIon ChannelIonsLaboratoriesLateralLeadLong-Term PotentiationMaintenanceMechanical StimulationMedicalMembraneMolecularMolecular and Cellular BiologyMotivationN-ethylmaleimide-sensitive proteinNamesNeuraxisNeuronsNociceptionNon-Steroidal Anti-Inflammatory AgentsOpioidPainPain managementPathway interactionsPeripheralPersonsPharmaceutical PreparationsPharmacologyPhasePlayPopulationPostsynaptic MembraneProsencephalonProtein IsoformsRecyclingRegulationResearchResolutionRoleSensoryStimulusStructureSurfaceSynapsesSynaptic plasticityTechnical ExpertiseTechniquesTestingabuse liabilitybehavioral studybrain researchcentral painchronic painchronic pain managementcingulate cortexexcitatory neuronexperienceextracellularimaging approachinflammatory paininhibitorinnovationmechanical allodyniamouse modelnerve injurynovel therapeuticsoptogeneticspain behaviorpain chronificationpain modelpain perceptionpain processingpain sensationpainful neuropathyprotein protein interactionreceptorresponseside effectspared nervetrafficking
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.
项目总结
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:
10580604 - 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:
8144875 - 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:
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:
相似海外基金
Examining the role of ASIC channels in pain through the development of subtype-specific ASIC channel modulators.
通过开发亚型特异性 ASIC 通道调制器来检查 ASIC 通道在疼痛中的作用。
- 批准号:
nhmrc : 511067 - 财政年份:2008
- 资助金额:
$ 23.4万 - 项目类别:
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