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.

安全有效地治疗疼痛仍然是全球未满足的医疗需求，这反过来又促成了

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