Validation of Neuropilin-1 receptor signaling in nociceptive processing

伤害感受处理中 Neuropilin-1 受体信号传导的验证

基本信息

批准号：
10774563
负责人：
Rajesh Khanna
金额：
$ 209.18万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10774563
关键词：
Absence of pain sensation Acute Acute Pain Adult Affect Affective Afferent Neurons Analgesics Angiogenic Factor Attenuated Behavior Behavioral Binding Biochemical Biological Assay Calcium Calcium Channel Central Nervous System Chemosensitization Chronic Clinical Cytoplasm Data Development Dorsal Future G-Protein-Coupled Receptors Genetic Human Hypersensitivity Intravenous Ion Channel Knock-in Mouse Knock-out Ligation Link Maintenance Malignant neoplasm of pancreas Mechanics Mediating Microglia Modeling Molecular Mus Neurons Neuropathy Neuropilin-1 Nociception Nociceptors Pain Pain Measurement Pathologic Pathway interactions Peripheral Phosphorylation Phosphotransferases Proteins Publishing Rattus Receptor Signaling Reporting Resolution Rodent Rodent Model Role SARS-CoV-2 spike protein Semaphorins Sensory Signal Induction Signal Pathway Signal Transduction Site Sodium Channel Spinal Spinal Cord Spinal Ganglia Spinal nerve structure Stimulus Surface Synapses Testing Thermal Hyperalgesias Traumatic Nerve Injury VEGFA gene Validation Vascular Endothelial Growth Factors Vertebral column Work animal pain antagonist antinociception axon guidance cancer pain chronic neuropathic pain chronic pain chronic pain management collapsin response mediator protein-2 efficacy testing efficacy validation experimental study extracellular humanized antibody in vivo inhibitor mechanical allodynia nerve injury nervous system development neurophysiology neurotransmission neurotransmitter release new therapeutic target next generation novel pain model pain reduction pain relief painful neuropathy pharmacologic prevent receptor response sensor spared nerve therapeutic target trafficking transmission process voltage

项目摘要

ABSTRACT Nociceptive pain is a protective response to harmful stimuli that is necessary to survival while nociplastic pain represents altered nociception arising from a sensitization of peripheral nociceptor neurons leading to subthreshold inputs eliciting a pain response. While studying a potential role for SARS-CoV-2 spike protein in pain, we identified Neuropilin 1 (NRP1) as a key receptor mediating the transduction of vascular endothelial growth factor-A (VEGFA) signaling to sensitize sensory neurons in models of nociplastic pain. In models of nerve injury pain, vascular endothelial growth factor-A (VEGFA) – an angiogenic factor – binds NRP1 and induces mechanical allodynia and thermal hyperalgesia. Pharmacological antagonism of NRP1 blocked VEGFA induced pain-like behaviors. This work demonstrated that NRP1 could be a novel therapeutic target with the potential to reverse chronic pain. Mechanistically, NRP1 sits upstream of a cytosolic protein – the collapsin response mediator protein 2 (CRMP2), a dual trafficking regulator of N-type voltage-gated calcium (CaV2.2) as well as voltage-gated sodium channels. We hypothesize that activation of the VEGFA/NRP1/CRMP2/ion channel pathway elicits sensitization of dorsal root ganglion neurons, consequently contributing to neuropathic pain states by enhancing excitatory synaptic input to dorsal spinal cord neurons. In this proposal, we test the hypothesis that interfering with VEGFA binding to NRP1 initiates an intracellular signaling cascade that, through CRMP2, leads to a decrease in sodium and calcium channel functional activity to decrease nociceptor activity culminating in reduced pain-like behaviors. We plan to test our hypothesis by using two chronic pain models to answer the following questions: 1. Does NRP1 signaling induce nociceptor sensitization and chronic hypersensitivity via CRMP2? 2. How does NRP1 signaling affect acute and chronic pain? 3. Are the anti-nociceptive effects of intrathecal NRP1inhibition mediated by targeting DRG neurons, microglia, or both? Completion of the proposed studies will allow: (i) validation of a novel target of chronic pain, (ii) use two chronic pain models to explore the breadth of applicability, and (iii) provide important information for development of a next generation of mechanism-based chronic pain medications. Overall, completion of these experiments will validate the role of NRP1 in nociceptive processing and will open opportunities for future therapeutic targeting of NRP1 for chronic pain treatment.

抽象的伤害性疼痛是对有害刺激的保护性反应，是生存所必需的，而伤害性疼痛则是生存所必需的代表由外周伤害感受器主导神经元的敏化引起的伤害感受改变在研究 SARS-CoV-2 刺突蛋白的潜在作用时，通过低于阈值的输入来引发疼痛反应。在疼痛中，我们发现 Neuropilin 1 (NRP1) 是介导血管转导的关键受体内皮生长因子-A (VEGFA) 信号使伤害性疼痛模型中的感觉神经元变得敏感。神经损伤疼痛模型中，血管内皮生长因子-A (VEGFA)（一种血管生成因子）结合 NRP1 并诱导机械异常性疼痛和热痛觉过敏。阻断 VEGFA 诱导的疼痛样行为这项工作证明 NRP1 可能是一种新的治疗方法。从机制上讲，NRP1 位于胞质蛋白的上游—— 塌陷反应介导蛋白 2 (CRMP2)，N 型电压门控钙的双重运输调节剂 (CaV2.2) 以及电压门控钠通道。 VEGFA/NRP1/CRMP2/离子通道通路引起背根神经节神经元的敏化，因此，通过增强背侧的兴奋性突触输入，导致神经性疼痛状态在本提案中，我们测试了干扰 VEGFA 结合的假设。 NRP1 启动细胞内信号级联，通过 CRMP2 导致钠含量减少和钙通道功能活性，以减少伤害感受器活性，最终减少类疼痛我们计划通过使用两个慢性疼痛模型来回答以下问题来检验我们的假设： 1. NRP1信号传导是否通过诱导伤害感受器敏化和慢性超敏反应 CRMP2？ 2. NRP1信号如何影响急性和慢性疼痛？ 3.鞘内NRP1抑制的抗伤害作用是通过靶向DRG介导的吗神经元、小胶质细胞，还是两者兼而有之？完成拟议的研究将允许：（i）验证慢性疼痛的新目标，（ii）使用两种慢性疼痛疼痛模型探索适用性的广度，以及（iii）为开发疼痛模型提供重要信息下一代基于机制的慢性疼痛药物。总的来说，这些实验的完成将验证 NRP1 在伤害性处理中的作用，并将开启 NRP1 未来治疗慢性疼痛治疗的机会。