Use of patient mis sense mutations in SCN9A to increase our understanding of the structure and function of sodium channels

本项目将探讨编码NaV1.7蛋白的SCN9A基因错义突变的发病机制。SCN9A的双等位基因无功能突变导致先天性疼痛不敏感（CIP）——受影响的个体在任何地方都感觉不到疼痛。大多数CIP突变是无意义的，因此不会产生蛋白质。然而，该项目从患者中选择的错义突变要有趣得多，并且可能揭示NaV1.7的运输、通道功能或基本相互作用伙伴的新方面。我将定义每种突变的致病机制，然后探索它们在开发镇痛疗法中的转化潜力。本项目涉及的技术包括单细胞电生理学，细胞和分子生物学，以及干细胞衍生伤害感受器的使用。该奖学金将由CIMR的Geoff Woods教授共同监督，他领导的团队研究疼痛感知障碍的遗传基础；以及MedImmune的约翰·林利博士，他领导一个电生理学团队探索新的疼痛信号机制。这个小组是CamPain的一部分；这是剑桥大学院系之间的合作，共同研究疼痛的细胞和分子基础，旨在改善疼痛的管理和治疗。

This project will explore the pathogenesis of missense mutations in the gene SCN9A encoding the protein NaV1.7. Bi-allelic non-functioning mutations in SCN9A cause Congenital Insensitivity to Pain (CIP) - where no pain is ever felt anywhere by affected individuals. The majority of CIP mutations are non-sense and thus cause no protein to be produced.However the mis-sense mutations chosen from patients for this project are far more interesting and likely to reveal novel aspects of the trafficking, channel function or essential interacting partners of NaV1.7. I will define the pathogenic mechanism of each mutation and then explore their translational potential in developing analgesic therapies. Techniques involved in this project include single cell electrophysiology, cell and molecular biology, and the use of stem cell derived nociceptors. The studentship will be supervised jointly by Professor Geoff Woods at CIMR, who leads a team investigating the genetic basis of disorders of pain sensing; and Dr John Linley at MedImmune who leads an electrophysiology team exploring novel pain signalling mechanisms. This group is part of CamPain; a collaboration between University of Cambridge Departments working together to investigate the cellular and molecular basis of pain with the aim of improving pain management and treatment.