Personalised mitochondrial health: a functional and multi-omic assessment to predict individual susceptibility to hepatoxicity of antiepileptic drugs

线粒体遗传学是个体化医疗中一个重要且研究不足的因素，这一认识正在增长。这一认识促使2014年在MRC药物安全科学中心（CDSS）建立了一个独特的综合计划，以确定线粒体遗传学在药物不良反应发生中的作用，该学生计划旨在继续和加强这一成功的研究计划。因此，本研究的目的是评估个体线粒体功能和遗传学在确定患者对一组与药物性肝损伤（DILI）相关的抗癫痫药物（AED）发生肝毒性的风险中的作用。将采用一种综合的多组学方法，其中功能，基因组学，蛋白质组学和代谢组学研究在专业生物信息学分析的支持下串联进行。许多抗癫痫药物（AED）与对肝脏的不良影响有关，并且已知会诱导线粒体功能障碍。这些包括一系列严重程度，从罕见的特异质危及生命，如与丙戊酸钠相关的肝毒性，可在少数患者中引起急性肝功能衰竭，到许多服用卡马西平等药物的患者遇到的肝脏ALT水平一过性升高。更清楚地了解诱发这些不良反应的遗传和机制因素及其严重程度将为更安全，有针对性地使用这些药物提供信息。这种方法需要使用一种先进的体外模型;一组肝脏特异性的transmitochondrial cybrids。基本上，在这种方法中，我们可以用来自志愿者或患者的mtDNA（使用血小板作为mtDNA供体）替换标准实验室模型细胞（HepG 2）的mtDNA（mtDNA），从而允许在恒定的核背景下重复检查单个mtDNA的影响。胞质杂交体将用于阐明线粒体功能障碍和细胞死亡之间的分子和化学途径，并进一步研究线粒体遗传和表观遗传变异对AED敏感性的影响。最后，定量代谢组学和蛋白质组学研究将寻求确定易感性或毒性的潜在生物标志物。

The realisation that mitochondrial genetics are an important, and under-researched, factor in personalised medicine is growing. This recognition prompted the establishment of a unique, integrative program at the MRC Centre for Drug Safety Science (CDSS) in 2014 in order to define the role of mitochondrial genetics in the onset of adverse drug reactions and this studentship seeks to continue and strengthen this successful research program. As such aim of this studentship is to evaluate the role of individual mitochondrial function and genetics in determining the risk of patients developing hepatotoxicity to a panel of anti-epileptic drugs (AED) associated with drug-induced liver injury (DILI). An integrated, multi-omic approach will be utilised in which functional, genomic, proteomic and metabolomic investigations are performed in tandem supported by specialised bioinformatic analysis. Many anti-epileptic drugs (AED) are associated with adverse effects on the liver and are known to induce mitochondrial dysfunction. These encompass a range of severity from rare idiosyncratic life-threatening , such as hepatotoxicity associated with sodium valproate which can cause acute liver failure in a small-number of patients, to transient, elevations in liver ALT levels, encountered by many patients taking drugs such as carbamazepine. Understanding more clearly the genetic and mechanistic factors predisposing to these adverse effects and their severity will inform the safer, targeted use of these drugs. This approach requires the use of an advanced in vitro model; a panel of liver-specific transmitochondrial cybrids. Essentially in this method we can replace the mitochondrial DNA (mtDNA) of a standard laboratory model cell (HepG2) with mtDNA from volunteers or patients using their platelets as the mtDNA donor, thus allowing the reproducible examination of the effects of individual mtDNA against a constant nuclear background. The cybrids will be utilised to elucidate the molecular and chemical pathways linking mitochondrial dysfunction and cell death and furthermore to investigate the effect of mitochondrial genetic and epigenetic variation on sensitivity to AEDs. Finally, quantitative metabolomic and proteomic investigations will seek to identify potential biomarkers of susceptibility or toxicity.