From Pain Resilience Genes Toward Therapeutic, Non-Opiate Modulation: An iPSC-Based Approach

从疼痛恢复基因到治疗性非阿片类药物调节：基于 iPSC 的方法

• 批准号: 10655583
• 负责人: Mark Estacion
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10655583
• 关键词: Afferent Neurons; Attenuated; Biological Assay; Black race; Blood; Blood specimen; Burn injury; Central Nervous System; Clinic; Closure by clamp; Detection; Development; Electrodes; Epigenetic Process; Epilepsy; Erythromelalgia; FDA approved; Family; Family member; Genes; Genetic; Genetic Models; Genomics; Goals; Human; Hypersensitivity; In Vitro; Individual; Inflammation Mediators; Inherited; Laboratories; Measures; Medical; Modeling; Mutation; Nerve; Neuronal Differentiation; Neurons; Nociceptors; Opioid; Pain; Pain management; Patients; Perception; Peripheral Nervous System; Peripheral Nervous System Diseases; Persons; Pharmaceutical Preparations; Phenotype; Population; Potassium; RBL2 gene; Rehabilitation therapy; Research; Spinal Ganglia; Spinal cord injury; Testing; Therapeutic; Translating; Translations; Variant; Veterans; Voltage-Gated Potassium Channel; Work; chronic pain; chronic pain management; clinical pain; effective therapy; exome sequencing; experience; exposed human population; gain of function; gain of function mutation; gene product; genetic variant; human subject; individual variation; induced pluripotent stem cell; inflammatory pain; kindred; limb amputation; neuronal excitability; neurotransmission; non-opioid analgesic; opioid epidemic; pain reduction; pain signal; pharmacologic; programs; resilience; response; social; treatment strategy

Safe and effective treatment for chronic pain is an 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 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 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 as modulators of pain in these patients. In this proposal, we will build upon our discovery of “pain resilience genes” and evaluate the potential of pharmacological modulators of Kv7 channels to reduce hyperexcitability of human sensory neurons derived from genetically validated subjects with chronic pain, as a way to identify safe and effective strategies that steer away from opioids in the treatment of chronic pain.

慢性疼痛的安全有效治疗是一种未满足的医疗需求，这反过来又导致了 鸦片危机疼痛的经历因人而异，有些人对疼痛相对有弹性。 与其他人相比，疼痛。虽然在临床上观察到疼痛的个体差异， 在实验室中精确建模，也没有仔细检查其机械基础。这部分是 因为疼痛涉及外周神经系统的检测和中枢神经系统的感知 系统，并可能受到许多因素，包括遗传，表观遗传，环境和社会。我们 对患有遗传性红斑性肢痛症（IEM）的血亲进行了研究，尽管他们携带了 相同的Nav1.7突变（S241 T）使我们能够鉴定在哺乳动物中表达的调节基因变体/突变。 使用全外显子组测序的感觉神经元作为这些患者的疼痛调节剂。在本提案中，我们 将在我们发现“疼痛恢复基因”的基础上评估药理学的潜力 Kv 7通道的调节剂，以降低源自遗传学的人感觉神经元的过度兴奋性。 经验证的慢性疼痛受试者，作为一种确定安全有效的策略， 阿片类药物治疗慢性疼痛