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

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

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NIGEL W BUNNETT其他文献

NIGEL W BUNNETT的其他文献

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{{ truncateString('NIGEL W BUNNETT', 18)}}的其他基金

Endosomal mechanisms signaling oral cancer pain
口腔癌疼痛的内体机制
  • 批准号:
    10786660
  • 财政年份:
    2023
  • 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:
    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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