Targeting Endosomal Receptors for Treatment of Chronic Pain

靶向内体受体治疗慢性疼痛

• 批准号: 9974866
• 负责人: NIGEL W BUNNETT
• 金额: $ 338.55万
• 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/9974866
• 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.

项目摘要/摘要 对常见形式的慢性疼痛的药物治疗无效，并受到副作用的困扰。我们的长- 学期目标是揭示疼痛/伤害性信号的机制并确定药物靶点。G蛋白偶联 受体(GPCRs)控制着包括疼痛在内的大多数病理生理过程，是34%的 治疗药物。GPCRs被认为只在质膜上起作用，在那里它们与 细胞外配体，并与细胞内G蛋白偶联。然而，从受伤和释放的激动剂 病变组织引起GPCRs在神经元内体的重新分布。这些内体GPCRs (EGPCRs)在亚细胞隔间产生持续的信号，控制离子通道的活动， 是慢性疼痛的基础。中心假设是，前伤害感受性eGPCRs的激活会产生 伤害性信号和大多数形式的慢性疼痛；eGPCRs的拮抗剂阻断伤害性信号和 是抗伤害性的。这项建议的基本原理是，eGPCR疼痛机制的发现将促进 开发选择性拮抗神经元中的eGPCRs并通过以下方式提供卓越止痛效果的药物 副作用更少。总体目标是发现慢性疼痛的潜在机制，并验证 治疗靶点。核心假设将通过追求三个具体目标来检验：1)发现 神经元亚细胞亚室中的eGPCR信号机制；生物物理和成像 将使用方法；纳米颗粒(NPs)将被设计成具有靶向神经元、促进 酸性内噬体内的内吞作用和释放eGPCR配体；2)发现 EGPCRs调节控制神经元活动的离子通道；神经元的离子通道活性和兴奋性 用电生理学来研究。NP包裹的药物探针将定义eGPCRs在神经元中的作用 激发；3)验证eGPCRs作为慢性炎症性、神经性和癌性疼痛的治疗靶点； 在三种疼痛模型中，NP包裹的eGPCR配体将与传统疗法进行比较。这个 提出的疼痛机制是一种新的解释，它解决了广泛的临床试验失败的谜团。 GPCR靶向药物。建议的创新延伸到NP方法，以探索机制和 验证目标。该建议具有临床意义，因为它验证了eGPCR靶标，提供了 止痛效果好，副作用少，适用于大多数顽固性慢性疼痛患者。