Adenylyl cyclase signaling in persistent pain
持续性疼痛中的腺苷酸环化酶信号传导
基本信息
- 批准号:10418657
- 负责人:
- 金额:$ 45.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:A kinase anchoring proteinAcuteAcute PainAdenylate CyclaseAffectAfferent NeuronsAmericanAnalgesicsAnimalsArthritisAutomobile DrivingBehavior assessmentBehavioralBiochemicalBrainCRISPR/Cas technologyCellsCessation of lifeChronicClinicalCo-ImmunoprecipitationsComplexCoupledCyclic AMPCyclic AMP-Dependent Protein KinasesDangerousnessDevelopmentDiabetic NeuropathiesDinoprostoneElectrophysiology (science)FamilyFamily memberG Protein-Coupled Receptor SignalingGene DeletionGenesGoalsHyperalgesiaHypersensitivityImageImmunohistochemistryIn VitroInflammatoryInjuryInterventionIntractable PainInvestigationIon ChannelIon Channel GatingKnock-outKnockout MiceLeadMalignant NeoplasmsMass Spectrum AnalysisMechanicsMediatingModelingMolecularMusNeurogenic InflammationNeuronsNeuropathyNeuropeptidesNociceptionNociceptorsOpioidOpioid AnalgesicsOpioid ReceptorPainPain managementPathologicPeripheralPersistent painPharmaceutical PreparationsPharmacologyPhosphoproteinsPhosphorylationPlayPostherpetic neuralgiaPre-Clinical ModelProductionProtein IsoformsReceptors, Adrenergic, alpha-2RegulationReporterResistanceRoleScaffolding ProteinSecond Messenger SystemsSignal PathwaySignal TransductionSignaling ProteinSpinal CordSpinal GangliaSustainable DevelopmentSyndromeSystemTRPV1 geneTestingWestern Blottingallodyniabasechronic painchronic pain managementclinically significanteffective interventioneffective therapyexperimental studyimprovedin vivoinnovationnon-opioid analgesicnovelpain chronificationpatch clampprescription opioidreceptorrecruitresponsescaffoldsocietal coststransmission process
项目摘要
Chronic pain affects more than 50 million Americans per year, resulting in extraordinary
personal and societal costs. Adding to the dilemma, deaths involving prescription opiate
analgesics have almost quadrupled in the last ten years. The clinical challenge of pain
management is underscored by evidence that chronic pain is mechanistically distinct from acute
pain, therefore a thorough understanding of the molecular and cellular mechanisms underlying
the transition to chronic pain is fundamental to improving and expanding treatment options.
Hyperalgesic priming is a compelling model of the transition to chronic pain in which an initial
injury resolves, but leaves the animal in a primed state in which a second insult induces a
greatly prolonged pain response. While previous studies have explored the development of
sustained mechanical hypersensitivity, we have adapted this model to examine sustained
hypersensitivity mediated by nociceptors expressing the heat-gated ion channel TRPV1, which
can drive pain in a range of inflammatory and neuropathic conditions. Experiments proposed
here will test the contribution to heat hyperalgesic priming of adenylyl cyclase isoform AC2,
which has not been previously characterized in sensory neurons, and which is insensitive to
inhibition by Gi/o-coupled receptors such as opioid receptors. Preliminary analysis indicates that
AC2 is highly expressed in TRPV1-expressing neurons and required for the manifestation of
heat hyperalgesic priming. Specific Aim 1 will examine the impact of AC2 gene deletion and
pharmacological inhibition on behavioral nociceptive thresholds at baseline, in acute
hyperalgesia and in the setting of hyperalgesic priming. Specific Aim 2 will determine whether
AC2 and the downstream effector Epac are functionally coupled through AKAP family member
scaffolding proteins by co-immunoprecipitation-mass spectrometry, and will determine the
impact of deleting identified AKAP genes on Epac signaling and nociceptor function in vitro
using a CRISPR/Cas9-based approach. Specific Aim 3 will determine the consequences for
Epac function of AC2 and AKAP gene deletion through Epac-dependent PKC phospho-
substrate profiling and behavioral assessment of heat hyperalgesia. This proposal will use
innovative approaches to explore novel mechanisms contributing to the development of
persistent hyperalgesia.
每年有超过5000万美国人受到慢性疼痛的影响
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DEREK C MOLLIVER其他文献
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{{ truncateString('DEREK C MOLLIVER', 18)}}的其他基金
Mitochondrial regulation of nociceptor function
伤害感受器功能的线粒体调节
- 批准号:
10644865 - 财政年份:2023
- 资助金额:
$ 45.99万 - 项目类别:
Purinergic G protein signal integration in nociceptors
伤害感受器中的嘌呤能 G 蛋白信号整合
- 批准号:
9049508 - 财政年份:2013
- 资助金额:
$ 45.99万 - 项目类别:
Purinergic G protein signal integration in nociceptors
伤害感受器中的嘌呤能 G 蛋白信号整合
- 批准号:
8838952 - 财政年份:2013
- 资助金额:
$ 45.99万 - 项目类别:
Purinergic G protein signal integration in nociceptors
伤害感受器中的嘌呤能 G 蛋白信号整合
- 批准号:
8500600 - 财政年份:2013
- 资助金额:
$ 45.99万 - 项目类别:
Pro- and Anti-Nociceptive Actions of P2y Nucleotide Receptors in Sensory Neurons
感觉神经元中 P2y 核苷酸受体的促伤害和抗伤害作用
- 批准号:
7501933 - 财政年份:2007
- 资助金额:
$ 45.99万 - 项目类别:
Pro- and Anti-Nociceptive Actions of P2y Nucleotide Receptors in Sensory Neurons
感觉神经元中 P2y 核苷酸受体的促伤害和抗伤害作用
- 批准号:
7371619 - 财政年份:2007
- 资助金额:
$ 45.99万 - 项目类别:
Pro- and Anti-Nociceptive Actions of P2y Nucleotide Receptors in Sensory Neurons
感觉神经元中 P2y 核苷酸受体的促伤害和抗伤害作用
- 批准号:
7878610 - 财政年份:2007
- 资助金额:
$ 45.99万 - 项目类别:
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