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.

原发感觉神经元的周围轴突的损害或丧失与两种临床综合征有关：周围神经性疼痛和周围神经病。神经性疼痛的治疗通常无效或与副作用有关，并且没有治疗周围神经病。为了解决这一问题，必须了解负责两者的机制，并确定可能适合新型治疗剂的发展。我的目标是在单个神经元水平上剖析响应物理轴突损伤，离子通道突变以及暴露于神经毒性癌症化学治疗剂的转录和功能变化，并探索与过度X值和轴突变性的程度。这将涉及几种不同方法的组合：将单细胞谱和疾病相关的功能变化相关联，确定患者茎衍生神经元的疾病易感性，高含量表型筛查，完整动物的人口成像，遗传编辑中的人口成像，以及在疼痛和感官损失行为的高时间和空间分辨率下的临时和空间分辨率。由于周围感觉轴突的身体破坏，由于电压门控钠通道突变而引起的小纤维神经病以及化学疗法诱导的周围神经病，该项目将重点关注神经性疼痛，并将检查这些综合症是否是一种具有感官神经元病理学的一部分或具有多种风险因素和机制因素和机制的一部分。