Investigation into the molecular function and pain profile of genetic variation in the irritant sensor TRPA1

即使随着健康的老龄化，疼痛也是一种越来越普遍的症状，对生活质量有很大的影响。因此，有效地预测、预防和治疗慢性疼痛将是迈向终身健康的重要一步。了解我们感受到疼痛的生物机制对于创造既有效又不会上瘾的新型镇痛药物至关重要。TRPA1是一种质膜离子通道，是神经元上检测威胁（伤害感受器）的传感器分子，包括热、冷和炎症信号/自由基。由于这个原因，TRPA1作为镇痛药的靶点和潜在调节疼痛易感性的基因很有兴趣，因此对常见和罕见（疾病相关）遗传变异的研究具有相当大的兴趣。在礼来公司，该学生将进行体外实验，以确定携带不同人类TRPA1变体的细胞如何对热刺激、致敏化学物质和药理化合物做出反应。他们还将使用最先进的高通量成像系统来确定离子通道的质膜运输，以及它们形成功能复合物。英国生物银行是一个无与伦比的资源，跟踪50万人的健康和福祉。预计2019年发布的数据包括前5万个外显子组和疼痛症状的详细信息。学生将对这些资源进行数据挖掘，找出trp通道基因型和疼痛表型之间的关联，从医院和全科医生记录、自我报告、成像和生物标志物中交叉链接的数据，以创建一个详细的档案，将伤害性通道的变异与人群疼痛表型联系起来。

Even with healthy aging, pain is an increasingly prevalent symptom, with a large impact on quality of life. Therefore the effective prediction, prevention and treatment of chronic pain will be a significant step towards lifelong health. Understanding the biological mechanisms by which we feel pain is vital to creating new analgesic medicines that are both effective and non-addictive. TRPA1 is a plasma membrane ion channel which is a sensor molecule on neurons that detect threats (nociceptors), including heat, cold and inflammatory signals / free radicals. For this reason TRPA1 is of interest as a target for analgesics and also as a gene potentially modulating susceptibility to pain Therefore the study of both common and rare (disease-associated) genetic variation is of considerable interest. At Eli Lilly the student will carry out in-vitro assays to ascertain how cells carrying different human TRPA1 variants respond to thermal stimuli, sensitising chemicals and pharmacological compounds. They will also use state-of the-art high throughput imaging systems to ascertain plasma membrane trafficking of the ion channels, and their formation into functional complexes.The UK Biobank is an unparalleled resource following the health and wellbeing of 500,000 individuals. Data releases expected in 2019 include the first 50,000 exomes and detailed information on pain symptoms. The student will data mine this resource for associations between TRP-channel genotypes and pain phenotypes, cross-linking data from hospital and GP records, self-report, imaging and biomarkers to create a detailed profile linking variants in nociceptive channels with population pain phenotypes.