疼痛一直是困扰医学界难题，发病机理不是十分清楚。许多离子通道基因突变与人类遗传性疼痛关联。Nav1.9是由SCN11A基因编码的电压门控型钠离子通道ɑ亚基第9个成员，它在伤害性感受器中呈特异分布，一些体内、外实验证明Nav1.9在疼痛中具有重要作用，但一直没有在人类疼痛异常患者中发现Nav1.9突变。2013年本课题组和Leipold等几乎同时报道Nav1.9突变与人类疼痛异常相关。但Nav1.9类似获得性功能突变所引起临床结果相反，Leipold等报道无痛，而我们发现的是发作性疼痛。为什么？本研究拟收集更多的疼痛异常患者对SCN11A进行突变检测，进一步确定突变类型；从体外（研究这些突变的电生理特性）和体内（KO和KI小鼠研究相似的功能突变导致的不同临床表现机制）水平研究Nav1.9突变导致疼痛异常发生的分子机制，为开发以Nav1.9为药靶的止痛药物奠定基础。

Pain was a medical puzzle. The pathologic mechanisms have remained elusive. Many ion channel genes have been associated with human genetic pain disorders. The SCN11A gene, encoding the ninth member of ɑ subunits of sodium channels (Nav1.9), is preferentially expressed in nociceptive neurons and plays important role in pain by verification of in vitro and vivo experiments. However, it was unclear whether mutations in SCN11A are associated with human genetic pain disorders. Untill 2013, Nav1.9 had been recognized as an important pain channel in humans reported by two independent research groups. One report by Leipold et al. showed that two individuals felt no pain carrying with the heterozygous mutation (L811P) in SCN11A; and another work by our research group studied two large Chinese families with many members affected by similar episodic pain symptoms, inherited in an autosomal-dominant pattern. Furthermore, we found a different mutation in each family in SCN11A/Nav1.9, R225C, and A808G, and Nav1.9 channels carrying either mutation passed more excitatory current than wild-type channels which was similar to the L811P mutation. However, new problems why similar gain-of-function mutations in the same SCN11A cause different pain syndromes are thrown up. In this study, we are aiming to further identify the Nav1.9 mutational category through mutation analysis in SCN11A by collecting more patients with pain disorders. We will then employ multidisciplinary approaches, including patch-clamp, molecular biology, protein biochemistry, immunocytochemical staining, fluorescence imaging, and knockout/knockin mouse strategy, to elucidate the molecular mechanisms underlying different pain disorders caused by SCN11A mutations. Therefore the proposed research is critically important for the further understanding of Nav1.9 functions in pain sensation, and also provides insights into analgesic drug developments based on Nav1.9 target.