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.

项目摘要/摘要 常见形式的慢性疼痛形式的药理学疗法无效，副作用困扰。我们的长期 术语目标是揭示疼痛/伤害感受信号传导的机制并定义药物靶标。 G蛋白耦合 受体（GPCR）控制大多数病情生理过程，包括疼痛，是34％的目标 治疗药物。 GPCR被认为仅在质膜上起作用，在那里它们与之相互作用 细胞外配体和夫妇到细胞内G蛋白。但是，激动者从受伤中释放出来 患病的组织引起了GPCR的重新分布到神经元内内体。这些内体GPCR （EGPCR）在控制离子通道活性的亚细胞隔室中产生持续信号 是慢性疼痛的基础。中心假设是，引起摄影性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的拮抗剂阻止伤害性信号传导和 具有抗伤害感受。该提议的理由是发现EGPCR疼痛机制将有助于 在神经元中有选择性地拮抗EGPCR并通过使用的药物开发 较少的副作用。总体目标是发现慢性疼痛的基础机制并验证 治疗靶标。中心假设将通过追求三个具体目标来检验：1）发现 神经元亚细胞隔室中EGPCR信号的机制；生物物理和成像 将使用方法；纳米颗粒（NP）将采用靶向神经元的组件，促进 酸性内体中的内吞和释放EGPCR配体； 2）发现的机制 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 用电生理学研究。 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，神经性和癌症疼痛的治疗靶标； 在三种疼痛模型中，将将NP包含的EGPCR配体与常规疗法进行比较。这 提出的疼痛机制是一种新的解释，可以解决广泛的临床试验失败的谜团 靶向GPCR的药物。该提案中的创新扩展到NP方法，以探测机制和 验证目标。该提案具有临床意义，因为它验证了提供的EGPCR目标 副作用较少的疼痛缓解疼痛，适用于大多数顽固性慢性疼痛的患者。