Shaping Pain:The Pain Resilience Project

塑造疼痛：疼痛恢复项目

• 批准号: 10228540
• 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/10228540
• 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.

安全有效的疼痛治疗仍然是全球未满足的医疗需求，这反过来又促进了 阿片类药物危机。疼痛的体验因人而异，有些人对疼痛的适应能力相对较强 与其他人相比感到痛苦。虽然在诊所观察到疼痛存在个体差异，但尚未得到证实 在实验室中精确建模，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，并可能受到许多因素的调节，包括遗传、表观遗传、环境和社会。 迄今为止，我们对患有遗传性红斑性肢痛症 (IEM) 的血亲进行了研究，尽管他们患有不同程度的疼痛， 携带相同的 Nav1.7 突变 (S241T)，使我们能够识别调节基因变异/突变 使用全外显子组测序在感觉神经元中表达，并指示一种特定基因 KCNQ2 和 建议另外三个基因作为这些患者的疼痛调节剂。毫无疑问还有额外的 影响 DRG 神经元放电和调节疼痛的分子。 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， 并接触其他具有 IEM 和不同个体间疼痛特征​​的家庭，以确定调节性 可能被开发成开发新疼痛治疗的靶标的基因。