Genetics of Drug Induced Cardiotoxicity

描述(由申请人提供)：我们感兴趣的是药物引起心脏毒性的遗传基础，以及这些遗传因素如何可能导致严重的药物不良反应，这些不良反应影响到一小部分人、治疗环境或两者。我们将进行全基因组筛选，以寻找影响心肌细胞收缩功能障碍或心律失常的因素，这些因素可能是由蒽环类药物和酪氨酸激酶抑制剂引起的收缩功能障碍或心律失常。该项目的最终研究目标是发现药物引起的心脏毒性变异的新机制、靶点和化学结构。建议的两阶段方法是首先在体外利用遗传多样性的小鼠胚胎干细胞来源的心肌细胞进行高通量全基因组相关性研究。这些研究中发现的基因将通过基因敲除来减少其表达，从而在人类IPS来源的心肌细胞中进行功能验证。这种方法利用了小鼠遗传学的作图能力和人类细胞反应的生物学相关性。

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.