Targeting Endosomal Receptors for Treatment of Chronic Pain

靶向内体受体治疗慢性疼痛

• 批准号: 10616927
• 负责人: NIGEL W BUNNETT
• 金额: $ 31.91万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10616927
• 关键词: Abate; Address; Administrative Supplement; Adverse effects; Affinity; Behavior; Cell Surface Receptors; Cell membrane; Cell surface; Cells; Chronic; Chronic Disease; Chronic inflammatory pain; Clathrin; Clinical Trials; Complex; Craniofacial Pain; Development; Differentiation and Growth; Disease; Drug Targeting; Electrophysiology (science); Encapsulated; Endocytosis; Endosomes; Engineering; Environment; Extracellular Fluid; Failure; Family; Foundations; Funding; G-Protein-Coupled Receptors; Gene Expression; Goals; Grant; Growth Factor; Growth Factor Receptors; Image; Inflammatory; Ion Channel; Ligand Binding; Ligands; Malignant Neoplasms; Measurement; Mediating; Mission; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; NGFR Protein; Nerve Growth Factors; Neurons; Neuropathy; Neuropilin-1; Nociception; Nociceptors; Pain; Pain management; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Pre-Clinical Model; Protein Tyrosine Kinase; Public Health; Receptor Activation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Research; Resistance; Role; Signal Pathway; Signal Transduction; Site; Stimulus; Therapeutic Intervention; Tissues; Treatment Efficacy; Trigeminal System; Tropomyosin; United States National Institutes of Health; Vascular Endothelial Growth Factors; Work; antagonist; antitumor drug; biophysical techniques; cancer pain; cancer therapy; cell type; chronic pain; chronic pain management; clinically significant; disability; experimental study; extracellular; imaging approach; improved; inhibitor; innovation; malignant mouth neoplasm; mechanical stimulus; nanoparticle; nanoparticle delivery; neurotransmission; nociceptive response; novel; pain relief; pain signal; painful neuropathy; parent grant; prevent; receptor; side effect; therapeutic target; tumor

PROJECT SUMMARY/ABSTRACT Pharmacologic therapy for common forms of chronic pain is ineffective and plagued with side effects. The long- term goal of the parent grant is to reveal mechanisms of pain/nociceptive signaling and define drug targets. The grant examines the mechanisms by which G protein-coupled receptors (GPCRs) within endosomes (eGPCRs) generate sustained signals in subcellular compartments that underlie persistent neuronal hyperexcitability and 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. Nanoparticles containing eGPCR amtagonists engineered to release cargo in the acidic endosomal environment are used to discover the mechanisms of eGPCR signaling and to validate eGPCRs as therapeutic targets for the treatment of chronic inflammatory, neuropathic and cancer pain. The administrative supplement builds on and extends the concepts of the parent grant to receptor tyrosine kinases (RTKs). RTKs are a family of cell surface receptors for growth factors. In addition to their well-known roles in proliferation and differentiation, certain RTKs also signal pain. Experiments will study endosomal signaling of tropomyosin receptor kinase A (TrkA), the high affinity receptor for nerve growth factor (NGF). NGF is produced by damaged tissues and tumors. NGF activates TrkA on nociceptors to mediate excitability and pain. Neuropilin 1 (NRP1) will also be studied, since preliminary results suggest that NRP1 is a previously unrecognized coreceptor for NGF with an important role in pain. NRP1 is transmembrane coreceptor for vascular endothelial growth factor, but its role in NGF signaling is unexplored. The Spefic Aim is to discover the mechanisms of eRTK signaling that regulate excitability of trigeminal nociceptors and validate eRTKs as a therapeutic target for chronic craniofacial pain. Biophysical and imaging approaches will be used to study the assembly and signaling of NGF/TrkA/NRP1 signalosomes in endosomes of mouse trigeminal nociceptors. Neuronal sensitization and activation of ion channels will be studied by electrophysiology and Ca2+ imaging. Preclinical models of trigeminal neuropathic pain and oral cancer pain will be studied in mice. NP-encapsulated antagonists and inhibitors of clathrin-mediated endocytosis will be used to discover the importance of endosomal signals for NGF-mediated hyperexcitability of nociceptors and to validate endosomal NGF/TrkA/NRP1 as therapeutic targets. The proposed pain mechanism is a novel explanation that resolves the enigma of widespread clinical trial failures of RTK-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 eRTK-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。长期 父授予的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。这 格兰特研究了内体内G蛋白偶联受体（GPCR）（EGPCR）的机制 在持续性神经元过度兴奋和的亚细胞室中产生持续信号 慢性疼痛。中心假设是，引起感受性EGPCR的激活会产生伤害感受信号传导 大多数形式的慢性疼痛； EGPCR的拮抗剂阻止伤害感受信号传导，并且具有抗伤害感受。 纳米颗粒，该纳米颗粒被设计为在酸性内体环境中释放货物的纳米颗粒 用于发现EGPCR信号传导的机制，并验证EGPCR作为治疗目标 慢性炎症，神经性和癌症疼痛的治疗。行政补充基于和 将父授予的概念扩展到受体酪氨酸激酶（RTKS）。 RTK是一个细胞表面的家族 生长因子的受体。除了它们在增殖和分化中众所周知的作用外，某些RTK 也表示疼痛。实验将研究tropomyosin受体激酶A（TRKA）的内体信号传导，高 神经生长因子（NGF）的亲和力受体。 NGF由受损的组织和肿瘤产生。 NGF激活 伤害感受器的TRKA介导兴奋性和疼痛。 Neuropilin 1（NRP1）也将被研究，因为初步 结果表明，NRP1是先前未识别的NGF的共感受器，在疼痛中起着重要作用。 NRP1 是血管内皮生长因子的跨膜共肽，但其在NGF信号中的作用尚未探索。 史上的目的是发现ERTK信号传导的机制，该机制调节了三叉神经的兴奋性 伤害感受器和验证ERTK是慢性颅面疼痛的治疗靶标。生物物理和成像 方法将用于研究内体中NGF/TRKA/NRP1信号的组装和信号 小鼠三叉神经伤害感受器。神经元敏化和离子通道的激活将通过 电生理学和CA2+成像。三叉神经性疼痛和口腔癌疼痛的临床前模型将 在小鼠中进行研究。 NP封装的拮抗剂和网格蛋白介导的内吞作用的抑制剂将用于 发现内体信号对NGF介导的伤害感受器的过度兴奋性的重要性并验证 内体NGF/TRKA/NRP1作为治疗靶标。提出的疼痛机制是一种新颖的解释， 解决了针对RTK靶向药物的广泛临床试验失败的谜团。提案中的创新扩展 到NP探测机制并验证目标的方法。该提议在临床上很重要，因为 它验证了一种ERTK-target，可提供较少的副作用的优质缓解疼痛，并且适用于大多数 患有顽固性慢性疼痛的患者。