Shaping Pain:The Pain Resilience Project

安全有效的疼痛治疗仍然是一个全球未得到满足的医疗需求，这反过来又促进了 阿片类药物危机。痛苦的体验因人而异，有些人对 比起其他人更痛苦。虽然在临床上观察到了疼痛的个体差异，但尚未发现 在实验室中精确建模，也没有仔细检查其机械基础。这是部分原因 因为疼痛既涉及外周神经系统的检测，也涉及中枢神经的感知 可能受到许多因素的调节，包括遗传、表观遗传、环境和社会因素。 我们到目前为止对遗传性红斑性肢痛症(IEM)的血缘亲属的研究，尽管有不同程度的疼痛 携带相同的Nav1.7突变(S241T)，使我们能够识别调制基因变体/突变 在感觉神经元中表达，并指示一个特定的基因KCNQ2和 提出了另外三个基因，作为这些患者的疼痛调节器。毫无疑问，还有其他 影响DRG神经元放电并调节疼痛的分子。 在这项拟议的工作中，我们将利用我们独特的诱导多潜能干细胞技术平台， 以及获得更多患有IEM和不同个体间疼痛特征的家庭，以确定调制 这些基因可能会被开发成开发新的疼痛治疗方法的靶点。

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.