Unravelling Mechanisms and Novel Therapeutic Targets for Peripheral Neuropathy and Neuropathic Pain (Diversity Supplement)

周围神经病变和神经性疼痛的揭示机制和新治疗靶点（多样性补充）

• 批准号: 10742137
• 负责人: CLIFFORD J WOOLF
• 金额: $ 8.84万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10742137
• 关键词: Afferent Neurons; Animals; Axon; Behavioral; Cells; Chemotherapy-induced peripheral neuropathy; Clinical; Development; Disease; Disease susceptibility; Evolution; Exposure to; Fiber; Genetic; Genetic Transcription; Goals; Image; Individual; Ion Channel; Link; Malignant Neoplasms; Molecular; Mutation; Neurons; Neuropathy; Pain; Pathology; Patients; Peripheral; Peripheral Nervous System Diseases; Phenotype; Population; Resolution; Risk Factors; Sensory; Sodium Channel; Syndrome; Time; axon injury; axonal degeneration; chemotherapeutic agent; design; neurotoxic; new therapeutic target; novel therapeutic intervention; novel therapeutics; painful neuropathy; response; side effect; stem; voltage

Title: Unravelling mechanisms and novel therapeutic targets for peripheral neuropathy and neuropathic pain Abstract Damage to or loss of the peripheral axons of primary sensory neurons is associated with two clinical syndromes: peripheral neuropathic pain and peripheral neuropathy. Treatment for neuropathic pain is typically ineffective or associated with side effects, and there is no treatment for peripheral neuropathy. To remedy this, it is essential that the mechanisms responsible for both are understood and targets identified that could be amenable to development of novel therapeutics. My goal is to dissect out at an individual neuron level the transcriptional and functional changes that occur over time in response to physical axonal injury, ion channel mutations and exposure to neurotoxic cancer chemotherapeutic agents, and explore the extent to which hyperexcitability and axon degeneration are linked. This will involve combinations of several different approaches: correlating single cell profiles and disease related functional changes, identifying disease susceptibility in patient stem derived neurons, high content phenotypic screens, population imaging in intact animals, genetic editing, and interrogation at high temporal and spatial resolution of behavioral surrogates of pain and sensory loss. The project will focus on neuropathic pain due to physical disruption of peripheral sensory axons, small fiber neuropathies due to voltage-gated sodium channel mutations and chemotherapy- induced peripheral neuropathy, and will examine if these syndromes are distinct or part of a spectrum of sensory neuron pathologies with overlapping risk factors and mechanisms.

标题：揭示周围神经病和神经病理性疼痛的机制和新的治疗靶点 摘要 初级感觉神经元外周轴突的损伤或丢失与两种临床症状有关 证候：周围神经病理性疼痛和周围神经病。神经性疼痛的治疗通常是 无效或与副作用相关，并且没有治疗周围神经病的方法。为了补救这一点， 至关重要的是，必须了解负责这两个问题的机制，并确定可能 顺应新疗法的发展。我的目标是在单个神经元水平上剖析 随着时间的推移发生的转录和功能变化，以响应物理轴突损伤，离子通道 突变和暴露于神经毒性癌症化疗药物，并探索 过度兴奋和轴突变性是有联系的。这将涉及几种不同的组合 方法：将单细胞图谱与疾病相关的功能变化联系起来，识别疾病 患者干细胞来源神经元的易感性、高含量表型筛选、完整的群体成像 动物、基因编辑和高时间和空间分辨率的行为代用品的讯问 疼痛和感觉丧失。该项目将专注于由于外周生理中断而引起的神经病理性疼痛 感觉轴突，电压门控钠通道突变和化疗引起的小纤维神经病- 诱导的周围神经病变，并将检查这些症状是不同的还是属于 具有重叠危险因素和机制的感觉神经元病理学。