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：周围神经病变和神经性疼痛的解开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缺失与两种临床表现有关， 综合征：周围神经性疼痛和周围神经病变。神经性疼痛的治疗通常是 无效或与副作用有关，并且没有治疗周围神经病变的方法。为了补救这一点， 至关重要的是，要了解负责这两个机制，并确定目标， 适合开发新的治疗方法。我的目标是在单个神经元水平上解剖出 转录和功能的变化，随着时间的推移发生响应物理轴突损伤，离子通道 突变和暴露于神经毒性癌症化疗药物，并探讨在何种程度上， 过度兴奋和轴突退化是有联系的这将涉及几种不同的 方法：将单细胞谱与疾病相关的功能变化相关联， 患者干细胞源性神经元的易感性，高含量表型筛选，完整的群体成像 动物，基因编辑，以及高时空分辨率的行为代理人的审讯。 疼痛和感觉丧失该项目将集中于神经性疼痛由于物理破坏外周 感觉轴突，小纤维神经病变，由于电压门控钠通道突变和化疗- 诱发的周围神经病变，并将检查这些综合征是否是不同的或频谱的一部分， 具有重叠风险因素和机制的感觉神经元病理。