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

即使健康老龄化，疼痛也是一种日益普遍的症状，对生活质量有很大影响。因此，有效预测、预防和治疗慢性疼痛将是迈向终身健康的重要一步。了解我们感受疼痛的生物机制对于创造既有效又不会上瘾的新止痛药至关重要。TRPA1是一种质膜离子通道，是神经元上的传感器分子，可以检测威胁(伤害性感受器)，包括热、冷和炎症信号/自由基。因此，TRPA1既是止痛药的靶点，又是潜在调节疼痛易感性的基因，因此对常见的和罕见的(疾病相关的)遗传变异的研究是相当有意义的。在礼来公司，这位学生将进行体外测试，以确定携带不同人类TRPA1变体的细胞如何对热刺激、增敏化学品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，以及它们形成的功能复合体。英国生物库是一个无与伦比的资源，关注着50万人的健康和福祉。预计将于2019年发布的数据包括前50,000个外显体和有关疼痛症状的详细信息。学生将从这一资源中挖掘TRP通道基因型别与疼痛表型之间的关联、来自医院和全科医生记录的交叉链接数据、自我报告、成像和生物标记物，以创建将伤害感受性通道中的变量与人群疼痛表型相关联的详细概况。

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.