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/摘要
药物治疗常见形式的慢性疼痛是无效的,并受到副作用的困扰。我们长久以来-
长期目标是揭示疼痛/伤害性信号传导的机制并确定药物靶点。G蛋白偶联
受体(GPCR)控制大多数病理生理过程,包括疼痛,并且是34%的
治疗药物GPCR被认为仅在质膜上起作用,在质膜上它们与
细胞外配体并与细胞内G蛋白偶联。然而,从损伤和
患病组织引起GPCR向神经元内体的再分布。这些内体GPCR
(eGPCR)在控制离子通道活性的亚细胞区室中产生持续的信号,
是慢性疼痛的基础核心假设是,原伤害感受eGPCR的激活产生了
伤害性信号传导和大多数形式的慢性疼痛; eGPCR的拮抗剂阻断伤害性信号传导,
是抗伤害的这一提议的基本原理是,eGPCR疼痛机制的发现将促进
开发选择性拮抗神经元中的eGPCR并提供上级疼痛缓解的药物,
更少的副作用。总体目标是发现慢性疼痛的潜在机制,并验证
治疗靶点中心假设将通过追求三个具体目标进行测试:1)发现
神经元亚细胞区室中eGPCR信号传导的机制;生物物理和成像
纳米粒子(NPs)将被设计成具有靶向神经元的成分,
内吞作用并在酸性内体中释放eGPCR配体; 2)发现
eGPCR调节控制神经元活性的离子通道;离子通道活性和神经元的兴奋性将
进行电生理学研究。NP包封的药物探针将定义eGPCR在神经元中的作用。
3)将eGPCR作为慢性炎性疼痛、神经性疼痛和癌症疼痛的治疗靶点;
将在三种疼痛模型中将NP包封的eGPCR配体与常规疗法进行比较。的
提出的疼痛机制是一种新的解释,解决了广泛的临床试验失败的谜团,
GPCR靶向药物。该提案的创新之处在于扩展到NP方法来探索机制,
确认目标该提案具有临床意义,因为它验证了eGPCR靶点,
上级止痛效果好,副作用少,适用于大多数顽固性慢性疼痛患者。
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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{{ 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
蛋白酶/PAR2/TRPV4轴与口腔癌疼痛
- 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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