Shaping Pain:The Pain Resilience Project

安全有效的疼痛治疗仍然是全球未得到满足的医疗需求，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。尽管在诊所中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。这部分是 因为疼痛涉及外周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。 到目前为止，我们对患有遗传性红斑性肢痛症（IEM）的血亲进行了研究，尽管他们有不同程度的疼痛， 携带相同的Nav1.7突变（S241 T），使我们能够识别调节基因变体/突变 使用全外显子组测序在感觉神经元中表达，并指示一个特定基因KCNQ 2， 这表明在这些患者中有三个额外的基因作为疼痛的调节剂。毫无疑问，还有更多的 影响DRG神经元放电和调节疼痛的分子。 在这项工作中，我们将利用我们独特的诱导多能干细胞技术平台， 并获得额外的家庭与IEM和不同的个体间的疼痛概况，以确定调节 这些基因可能被开发成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.