Genetics of Drug Induced Cardiotoxicity

描述（由申请人提供）：我们对药物诱导的心脏毒性的遗传基础感兴趣，以及这些遗传因素如何可能导致严重的药物不良反应，这些不良反应影响一小部分但重要的个体，治疗环境，或两者。我们将对蒽环类药物和酪氨酸激酶抑制剂引起的心肌细胞收缩缺陷或心律失常的影响因素进行全基因组筛选。该项目的最终研究目标是发现药物诱导心脏毒性变异性的新机制、靶点和化学结构。提出的两阶段方法是首先使用遗传多样化的小鼠ES衍生心肌细胞在体外进行高通量全基因组关联研究。在这些研究中发现的基因将通过基因敲低来减少其表达，从而在人类IPS衍生的心肌细胞中得到功能验证。这种方法利用了小鼠遗传学与人类细胞反应的生物学相关性的制图能力。

DESCRIPTION (provided by applicant): We are interested in the genetic basis of drug induced cardiotoxicity, and how these genetic factors may underlie serious adverse drug reactions that affect a small but significant fraction of individuals, therapeutic circumstances, o both. We will conduct genomewide screens for factors affecting cardiomyocyte contractile deficit or arrhythmia caused by anthracycline and tyrosine kinase inhibitor induced contractile deficit or arrhythmia. The ultimate research goal of this project is to discover novel mechanisms, targets, and chemical structures underlying variability in drug induced cardiotoxicity. The proposed two-stage approach is to first conduct high throughput genomewide association studies in vitro using genetically diverse mouse ES derived cardiomyocytes. The genes found in those studies will be functionally validated in human IPS derived cardiomyocytes by reducing their expression via gene knockdown. This approach takes advantage of the mapping power of mouse genetics with the biological relevance of human cell responses.