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

慢性疼痛的安全有效治疗是一项未满足的医疗需求，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。我们的 对患有遗传性红斑性肢痛症 (IEM) 的血亲进行的研究，尽管携带红斑性肢痛症，但仍伴有不同程度的疼痛 相同的 Nav1.7 突变 (S241T) 使我们能够识别在 使用全外显子组测序作为这些患者疼痛的调节剂的感觉神经元。在这个提案中，我们 将建立在我们发现“疼痛恢复基因”的基础上，并评估药理学的潜力 Kv7 通道调节剂，可减少源自遗传的人类感觉神经元的过度兴奋 验证患有慢性疼痛的受试者，作为一种确定安全有效的策略的方法，以避免 阿片类药物治疗慢性疼痛。

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.