Unravelling mechanisms and novel therapeutic targets for peripheral neuropathy and neuropathic pain

周围神经病和神经性疼痛的揭示机制和新治疗靶点

• 批准号: 10320363
• 负责人: CLIFFORD J WOOLF
• 金额: $ 132.75万
• 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/10320363
• 关键词: Afferent Neurons; Animal Genetics; Axon; Behavioral; Cells; Chemotherapy-induced peripheral neuropathy; Clinical; Development; Disease; Disease susceptibility; Evolution; Exposure to; Fiber; 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

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.

初级感觉神经元的外周轴突的损伤或丧失与两种临床综合征相关：外周神经性疼痛和外周神经病。神经性疼痛的治疗通常是无效的或与副作用相关，并且没有治疗周围神经病变的方法。为了解决这一问题，至关重要的是要了解两者的机制，并确定可能适合开发新疗法的靶点。我的目标是在单个神经元水平上剖析随着时间的推移在物理轴突损伤、离子通道突变和暴露于神经毒性癌症化疗剂时发生的转录和功能变化，并探索过度兴奋和轴突变性的联系程度。这将涉及几种不同方法的组合：将单细胞谱与疾病相关的功能变化相关联，鉴定患者干细胞衍生神经元中的疾病易感性，高含量表型筛选，完整动物中的群体成像，基因编辑，以及以高时间和空间分辨率询问疼痛和感觉丧失的行为替代物。该项目将重点关注由于外周感觉轴突的物理破坏引起的神经性疼痛，由于电压门控钠通道突变引起的小纤维神经病和化疗引起的周围神经病，并将检查这些综合征是否是独特的或具有重叠风险因素和机制的感觉神经元病理谱的一部分。