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.

项目总结/摘要 药物治疗常见形式的慢性疼痛是无效的，并受到副作用的困扰。很长的- 该基金的长期目标是揭示疼痛/伤害性信号传导的机制并确定药物靶点。的 格兰特研究了核内体G蛋白偶联受体（eGPCR） 在亚细胞区室中产生持续的信号，这些信号是持续神经元过度兴奋的基础， 慢性疼痛中心假设是，原伤害感受eGPCR的激活产生伤害感受信号 和大多数形式的慢性疼痛; eGPCR的拮抗剂阻断伤害性信号传导并且是抗伤害性的。 含有被工程化以在酸性内体环境中释放货物的eGPCR拮抗剂的纳米颗粒 用于发现eGPCR信号传导的机制，并验证eGPCR作为治疗靶点， 治疗慢性炎性、神经性和癌症疼痛。行政补助金的基础是 将亲本授权的概念扩展到受体酪氨酸激酶（RTK）。RTK是细胞表面的一个家族， 生长因子受体。除了它们在增殖和分化中的众所周知的作用之外，某些RTK还可以在细胞增殖和分化中发挥作用。 也是疼痛的信号实验将研究原肌球蛋白受体激酶A（TrkA）的内体信号传导，高表达的TrkA蛋白， 神经生长因子（NGF）的亲和受体。NGF是由受损的组织和肿瘤产生的。NGF激活 TrkA对伤害感受器介导兴奋性和疼痛。神经纤毛蛋白1（NRP 1）也将进行研究，因为初步 结果提示NRP 1是一种以前未被认识到的在疼痛中具有重要作用的NGF辅助受体。NRP1 是血管内皮生长因子的跨膜共受体，但其在NGF信号转导中的作用尚未研究。 本研究的具体目的是探讨eRTK信号对三叉神经兴奋性的调节机制 并验证eRTK作为慢性颅面疼痛的治疗靶点。生物物理和成像 本研究将采用多种方法研究NGF/TrkA/NRP 1信号体在核内体中的组装和信号传导 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Ca 2+成像。三叉神经病理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包封的网格蛋白介导的内吞作用的拮抗剂和抑制剂将用于 发现内体信号对NGF介导的伤害感受器过度兴奋的重要性，并验证 内体NGF/TrkA/NRP 1作为治疗靶点。提出的疼痛机制是一种新颖的解释， 解决了RTK靶向药物广泛临床试验失败的谜团。提案中的创新延伸到 到NP方法来探测机制和验证目标。该建议具有临床意义，因为 它验证了一种eRTK目标，可提供上级疼痛缓解，副作用较少，适用于大多数 顽固性慢性疼痛患者。