Targeting Endosomal Receptors for Treatment of Chronic Pain

靶向内体受体治疗慢性疼痛

• 批准号: 10458307
• 负责人: NIGEL W BUNNETT
• 金额: $ 22.29万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10458307
• 关键词: Address; Afferent Neurons; Agonist; Calcitonin Gene-Related Peptide; Cell membrane; Chronic inflammatory pain; Clathrin; Clinical; Clinical Trials; Development; Disease; Drug Targeting; Early Endosome; Electrophysiology (science); Encapsulated; Endocytosis; Endosomes; Environment; Failure; Family; Foundations; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic Transcription; Goals; Human; Ion Channel; Ligands; Mediating; Mission; Modeling; Mus; Neurons; Nociception; Nociceptors; Opioid Receptor; PAR-2 Receptor; Pain; Pain management; Patients; Pharmaceutical Preparations; Pharmacology; Physiological Processes; Pre-Clinical Model; Process; Property; Public Health; Research; Role; Sensory; Signal Transduction; Signaling Protein; Stimulus; Substance P; Substance P Receptor; Testing; Therapeutic; Tissues; Translations; Treatment Efficacy; United States National Institutes of Health; Validation; Work; addiction; biophysical techniques; cancer pain; chronic pain; clinically significant; comparative efficacy; conventional therapy; design; disability; drug development; drug discovery; extracellular; imaging approach; inflammatory pain; injured; innovation; mouse model; nanoparticle; novel; pain model; pain relief; painful neuropathy; receptor; side effect; therapeutic target; transmission process

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.

项目概要/摘要 对于常见形式的慢性疼痛的药物治疗无效并且存在副作用。我们的长期 术语目标是揭示疼痛/伤害性信号传导机制并定义药物靶点。 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% 的疾病的目标 治疗药物。 GPCR 被认为仅在质膜上发挥作用，在那里它们与 胞外配体并与胞内 G 蛋白偶联。然而，激动剂从受伤和 患病组织引起 GPCR 重新分布至神经元内体。这些内体 GPCR (eGPCR) 在亚细胞区室中产生持续信号，控制离子通道活动， 是慢性疼痛的基础。核心假设是，刺激性 eGPCR 的激活会产生 伤害性信号传导和大多数形式的慢性疼痛； eGPCR 拮抗剂可阻断伤害性信号传导 具有抗伤害性。该提案的基本原理是 eGPCR 疼痛机制的发现将有助于 开发选择性拮抗神经元 eGPCR 并提供卓越疼痛缓解的药物 副作用更少。总体目标是发现慢性疼痛的机制并验证 治疗目标。将通过追求三个具体目标来检验中心假设：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 将使用的方法；纳米颗粒（NP）将采用针对神经元的成分进行设计，促进 在酸性内体中内吞并释放 eGPCR 配体； 2) 发现其机制 eGPCR 调节控制神经元活动的离子通道；离子通道的活性和神经元的兴奋性 通过电生理学进行研究。 NP 封装的药物探针将定义 eGPCR 在神经元中的作用 励磁; 3）验证eGPCR作为慢性炎症、神经性疼痛和癌性疼痛的治疗靶点； NP 封装的 eGPCR 配体将在三种疼痛模型中与传统疗法进行比较。这 提出的疼痛机制是一种新颖的解释，解决了广泛的临床试验失败的谜团 GPCR 靶向药物。该提案的创新延伸到了NP方法来探索机制和 验证目标。该提案具有临床意义，因为它验证了 eGPCR 目标，该目标提供 止痛效果优越，副作用较少，适用于大多数顽固性慢性疼痛患者。