Shaping Pain:The Pain Resilience Project

塑造疼痛：疼痛恢复项目

• 批准号: 10534105
• 负责人: Stephen Waxman
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534105
• 关键词: Afferent Neurons; Blood; Burn injury; CCR5 gene; Candidate Disease Gene; Characteristics; Clinic; Closure by clamp; Data; Databases; Detection; Development; Disease model; Epigenetic Process; Erythromelalgia; Family; Genes; Genetic; Genetic Models; Goals; Human; ITPR1 gene; Individual; Individual Differences; Inherited; Laboratories; Libraries; Link; Medical; Membrane; Modeling; Molecular; Mutation; Nerve; Neuraxis; Neurons; Pain; Pain management; Patients; Perception; Peripheral; Peripheral Nervous System; Peripheral Nervous System Diseases; Persons; Phenotype; Property; Publishing; RNA Splicing; Rehabilitation therapy; Role; Shapes; Sodium Channel; Spinal cord injury; System; Therapeutic; Variant; Veterans; Work; base; chronic pain; disease phenotype; disease-in-a-dish; effective therapy; exome sequencing; experience; genetic variant; human disease; human subject; individual variation; induced pluripotent stem cell; induced pluripotent stem cell technology; innovation; kindred; limb amputation; member; mutant; novel; opioid epidemic; pain signal; painful neuropathy; resilience; social; transcriptome sequencing; voltage clamp

Safe and effective treatment for pain remains a global unmet medical need, which in turn has contributed to the opioid crisis. The experience of pain varies from person to person, with some individuals relatively resilient to pain compared to others. Individual-to-individual variation in pain, while observed in the clinics, has not been accurately modeled in the laboratory nor has its mechanistic underpinnings carefully examined. This is partially because pain involves both detection by the peripheral nervous system and perception in the central nervous system, and may be modulated by many factors including genetic, epigenetic, environmental and social. Our studies thus far of blood relatives with inherited erythromelalgia (IEM) with varying degrees of pain despite carrying the same Nav1.7 mutation (S241T), have allowed us to identify modulatory gene variants/mutations expressed in sensory neurons using whole exome sequencing, and indict one specific gene, KCNQ2, and suggest three additional genes, as modulators of pain in these patients. There are undoubtedly additional molecules that influence DRG neuron firing and modulate pain. In this proposed work, we will capitalize on our unique platform of induced pluripotent stem cell technology, and access to additional families with IEM and varying inter-individual pain profiles, to identify modulatory genes that might be developed into targets for the development of new pain treatments.

安全有效治疗疼痛仍然是全球未满足的医疗需求，这反过来促成 阿片类药物危机。痛苦的经历因人而异，有些人相对有抵抗力 与其他人相比疼痛。疼痛的个体与个体变化，虽然在诊所中观察到 准确地在实验室建模，也没有仔细检查其机械基础。这是部分 因为疼痛涉及周围神经系统的检测和中枢神经的感知 系统，可能会受到许多因素的调节，包括遗传，表观遗传学，环境和社会。 到目前为止，我们的研究具有遗传性红细胞毛（IEM）的血液亲戚，尽管 携带相同的NAV1.7突变（S241T），使我们能够识别调节基因变体/突变 使用整个外显子组测序在感觉神经元中表达，并起诉一个特定基因KCNQ2和 建议另外三个基因，作为这些患者疼痛的调节剂。毫无疑问还有其他 影响DRG神经元发射并调节疼痛的分子。 在这项拟议的工作中，我们将利用我们独特的诱导多能干细胞技术平台， 并获得具有IEM和不同个体间疼痛特征​​的其他家庭，以识别调节 可能发展为开发新疼痛治疗的靶标的基因。

项目成果

Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability.

• DOI: 10.3389/fphar.2023.1138556
• 发表时间: 2023
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6

KCNQ variants and pain modulation: a missense variant in Kv7.3 contributes to pain resilience.

• DOI: 10.1093/braincomms/fcab212
• 发表时间: 2021
• 期刊: Brain communications
• 影响因子: 4.8
• 作者: Yuan JH;Estacion M;Mis MA;Tanaka BS;Schulman BR;Chen L;Liu S;Dib-Hajj FB;Dib-Hajj SD;Waxman SG
• 通讯作者: Waxman SG