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 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。长的- 家长基金的任期目标是揭示疼痛/伤害信号的机制，并确定药物靶点。这个 格兰特研究了内小体中的G蛋白偶联受体(GPCRs)的机制 在亚细胞隔间产生持续的信号，这些信号是持续性神经元超兴奋性和 慢性疼痛。中心假设是eGPCRs的激活产生伤害性信号。 和大多数形式的慢性疼痛；eGPCRs的拮抗剂阻断伤害性信号，具有抗伤害性。 含有eGPCR激活剂的纳米颗粒被设计成在酸性内噬体体环境中释放货物 被用来发现eGPCRs的信号转导机制，并验证eGPCRs作为治疗靶点 治疗慢性炎症性、神经性和癌性疼痛。行政副刊以和为基础 将亲本授予的概念扩展到受体酪氨酸激酶(RTK)。RTK是一个细胞表面家族 生长因子受体。除了在增殖和分化中的众所周知的作用外，某些RTK 也是疼痛的信号。实验将研究原肌球蛋白受体激酶A(TrkA)的内体信号转导。 神经生长因子(NGF)亲和受体。NGF是由受损的组织和肿瘤产生的。NGF被激活 伤害性感受器上的TrkA可调节兴奋性和疼痛。还将研究神经粘连蛋白1(Nrp1)，因为初步 结果表明，Nrp1是一种以前未被认识的NGF辅助受体，在疼痛中起着重要作用。Nrp1 是血管内皮生长因子的跨膜辅助受体，但其在NGF信号转导中的作用尚不清楚。 其具体目的是发现eRTK信号调节三叉神经兴奋性的机制。 伤害性感受器和验证eRTK作为慢性颅面疼痛的治疗靶点。生物物理和成像 将采用多种方法研究NGF/TrkA/Nrp1信号体在内体中的组装和信号传递 小鼠三叉神经伤害性感受器。神经元的敏化和离子通道的激活将通过 电生理学和钙离子成像。三叉神经病理性疼痛和口腔癌疼痛的临床前模型将 在小鼠身上进行研究。NP包裹的笼蛋白介导的内吞作用的拮抗剂和抑制剂将用于 发现内体信号在NGF介导的伤害性感受器超兴奋性中的重要性并验证 以NGF/TrkA/Nrp1为治疗靶点。提出的疼痛机制是一种新的解释， 解开了RTK靶向药物广泛临床试验失败的谜团。提案中的创新扩展了 以NP方法探索其作用机制并验证靶点。这项建议具有临床意义，因为 它验证了eRTK靶标，它提供了更好的止痛效果，副作用更少，适用于大多数 患有顽固性慢性疼痛的患者。