Genetics of Drug Induced Cardiotoxicity

药物引起的心脏毒性的遗传学

• 批准号: 9015442
• 负责人: Ted Choi
• 金额: $ 49.36万
• 依托单位: PREDICTIVE BIOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9015442
• 关键词: Affect; Algorithms; Anthracyclines; Arrhythmia; Biological; Biological Assay; Biology; Candidate Disease Gene; Cardiac Myocytes; Cardiotoxicity; Cells; Chemical Structure; Computer software; Development; Disease; Dose; Evaluation; Gene Expression; Genes; Genetic; Goals; Government; Head; Health; Heart; Human; In Vitro; Individual; Maps; Mus; Persons; Pharmaceutical Preparations; Phase; Quantitative Trait Loci; RNA; Reaction; Research; Resources; Reverse Transcriptase Polymerase Chain Reaction; Small Business Innovation Research Grant; Source; Speed; Staging; Testing; Therapeutic; Tissues; Tyrosine Kinase Inhibitor; Validation; Viral; base; design; embryonic stem cell; follow-up; genome wide association study; genome-wide; graphical user interface; improved; induced pluripotent stem cell; innovation; instrument; interest; knock-down; novel; response; small hairpin RNA; trait; user-friendly; vector

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.

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构成严重的严重不良药物反应，这些反应影响了少数但显着的个体，治疗状况，o两者都受到治疗。我们将进行全基因组筛查，以影响由蒽环类和酪氨酸激酶抑制剂引起的心肌细胞收缩赤字或心律不齐的因素，引起了收缩性赤字或心律不齐。该项目的最终研究目标是发现药物诱导的心脏毒性可变性的新型机制，靶标和化学结构。所提出的两阶段方法是使用遗传多样的小鼠ES衍生的心肌细胞在体外首先在体外进行高通量基因组关联研究。这些研究中发现的基因将在人IPS衍生的心肌细胞中通过降低基因敲低的表达来验证。该方法利用了小鼠遗传学的映射能力，其生物学反应的生物学相关性。