Targeting Endosomal Receptors for Treatment of Chronic Pain
靶向内体受体治疗慢性疼痛
基本信息
- 批准号:9974866
- 负责人:
- 金额:$ 338.55万
- 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:2020-09-15 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAfferent NeuronsAgonistCalcitonin Gene-Related PeptideCell membraneChronic inflammatory painClathrinClinicalClinical TrialsDevelopmentDiseaseDrug TargetingEarly EndosomeElectrophysiology (science)EncapsulatedEndocytosisEndosomesEnvironmentFailureFamilyFoundationsG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGTP-Binding ProteinsGenetic TranscriptionGoalsHumanIon ChannelLigandsMediatingMissionModelingMusNeuronsNociceptionNociceptorsOpioid ReceptorPAR-2 ReceptorPainPain managementPatientsPharmaceutical PreparationsPharmacologyPhysiological ProcessesPre-Clinical ModelProcessPropertyPublic HealthResearchRoleSensorySignal TransductionSignaling ProteinStimulusSubstance PSubstance P ReceptorTestingTherapeuticTissuesTranslationsTreatment EfficacyUnited States National Institutes of HealthValidationWorkaddictionbiophysical techniquescancer painchronic painclinically significantcomparative efficacyconventional therapydesigndisabilitydrug developmentdrug discoveryextracellularimaging approachinflammatory paininjuredinnovationmouse modelnanoparticlenovelpain modelpain reliefpainful neuropathyreceptorside effecttherapeutic targettransmission process
项目摘要
PROJECT SUMMARY/ABSTRACT
Pharmacologic therapy for common forms of chronic pain is ineffective and plagued with side effects. Our long-
term goal is to reveal mechanisms of pain/nociceptive signaling and define drug targets. G protein-coupled
receptors (GPCRs) control most patho-physiological processes, including pain, and are the target of 34% of
therapeutic drugs. GPCRs are considered to function solely at the plasma membrane, where they interact with
extracellular ligands and couple to intracellular G proteins. However, agonists released from injured and
diseased tissues evoke redistribution of GPCRs to endosomes in neurons. These endosomal GPCRs
(eGPCRs) generate sustained signals in subcellular compartments that control the ion channel activity that
underlies chronic pain. The central hypothesis is that activation of pronociceptive eGPCRs produces
nociceptive signaling and most forms of chronic pain; antagonists of eGPCRs block nociceptive signaling and
are anti-nociceptive. The rationale for this proposal is that discovery of eGPCR pain mechanisms will facilitate
development of drugs that selectively antagonize eGPCRs in neurons and provide superior pain relief with
fewer side effects. The overall objectives are to discover mechanisms underlying chronic pain and validate a
therapeutic target. The central hypothesis will be tested by pursuing three specific aims: 1) Discover the
mechanisms of eGPCR signaling in subcellular compartments of neurons; biophysical and imaging
approaches will be used; nanoparticles (NPs) will be designed with components that target neurons, promote
endocytosis and release eGPCR ligands in the acidic endosome; 2) Discover the mechanisms by which
eGPCRs regulate ion channels that control neuron activity; ion channel activity and excitability of neurons will
be studied with electrophysiology. NP-encapsulated drug probes will define the role of eGPCRs in neuronal
excitation; 3) Validate eGPCRs as a therapeutic target for chronic inflammatory, neuropathic and cancer pain;
NP-encapsulated eGPCR ligands will be compared to conventional therapy in three pain models. The
proposed pain mechanism is a novel explanation that resolves the enigma of widespread clinical trial failures of
GPCR-targeted drugs. Innovation in the proposal extends to the NP approach to probe the mechanism and
validate the target. The proposal is clinically significant because it validates an eGPCR-target that offers
superior pain relief with fewer side-effects and is applicable to most patients with intractable chronic pain.
项目总结/文摘
项目成果
期刊论文数量(0)
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{{ truncateString('NIGEL W BUNNETT', 18)}}的其他基金
Targeting Endosomal Receptors for Treatment of Chronic Pain
靶向内体受体治疗慢性疼痛
- 批准号:
10616927 - 财政年份:2022
- 资助金额:
$ 338.55万 - 项目类别:
Trafficking-Dependent Signaling of Pain by Protease-Activated Receptors
蛋白酶激活受体的贩运依赖性疼痛信号传导
- 批准号:
10174921 - 财政年份:2020
- 资助金额:
$ 338.55万 - 项目类别:
Trafficking-Dependent Signaling of Pain by Protease-Activated Receptors
蛋白酶激活受体的贩运依赖性疼痛信号传导
- 批准号:
10093340 - 财政年份:2020
- 资助金额:
$ 338.55万 - 项目类别:
Targeting Endosomal Receptors for Treatment of Chronic Pain
靶向内体受体治疗慢性疼痛
- 批准号:
10458307 - 财政年份:2020
- 资助金额:
$ 338.55万 - 项目类别:
Protease/PAR2/TRPV4 Axis and Oral Cancer Pain
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- 批准号:
10020473 - 财政年份:2019
- 资助金额:
$ 338.55万 - 项目类别:
Protease/PAR2/TRPV4 Axis and Oral Cancer Pain
蛋白酶/PAR2/TRPV4轴与口腔癌疼痛
- 批准号:
10321672 - 财政年份:2018
- 资助金额:
$ 338.55万 - 项目类别:
Trafficking-Dependent Signaling of Pain by Protease-Activated Receptors
蛋白酶激活受体的贩运依赖性疼痛信号传导
- 批准号:
9757759 - 财政年份:2018
- 资助金额:
$ 338.55万 - 项目类别:
Endosomal Platforms for Neuropeptide Receptor Signaling
神经肽受体信号转导的内体平台
- 批准号:
10093292 - 财政年份:2017
- 资助金额:
$ 338.55万 - 项目类别:
Endosomal Platforms for Neuropeptide Receptor Signaling
神经肽受体信号转导的内体平台
- 批准号:
10200907 - 财政年份:2017
- 资助金额:
$ 338.55万 - 项目类别:
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