Genetics of Drug Induced Cardiotoxicity

描述（由申请人提供）：我们感兴趣的是药物诱导的心脏毒性的遗传基础，以及这些遗传因素如何成为严重药物不良反应的基础，这些不良反应影响了一小部分但很重要的个体、治疗环境或两者。我们将进行全基因组筛选，寻找蒽环类药物和酪氨酸激酶抑制剂诱导的心肌收缩缺陷或心律失常的影响因素。该项目的最终研究目标是发现药物诱导的心脏毒性的新机制、靶点和化学结构。所提出的两阶段方法是首先使用遗传多样性小鼠ES衍生的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在人IPS衍生的心肌细胞中通过经由基因敲低降低其表达来进行功能验证。这种方法利用了小鼠遗传学的映射能力与人类细胞反应的生物相关性。

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.