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Characterization and Genetics of KI toxicity in iPSC-derived cardiomyocytes

iPSC 衍生心肌细胞中 KI 毒性的特征和遗传学

基本信息

批准号：
9917814
负责人：
ULRICH BROECKEL
金额：
$ 74.41万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917814
关键词：
Adverse effects Animal Model Animals Antineoplastic Agents Biological Assay Cancer Patient Cardiac Myocytes Cardiotoxicity Cell Differentiation process Cell Line Cells Collaborations Collection Congestive Heart Failure Data Development Disease Marker Disease model Dose Exhibits Expression Profiling Functional disorder Funding Future Genetic Genetic Diseases Genetic Markers Genome Goals Grant Heart failure Human Individual Infrastructure Knowledge Lactate Dehydrogenase Life Measures Medicine Modeling Molecular Molecular Genetics Morbidity - disease rate Myocardial dysfunction National Heart, Lung, and Blood Institute Participant Pathway Analysis Pathway interactions Patients Pharmaceutical Preparations Phenotype Property Quantitative Trait Loci Reaction Time Research Risk Risk Factors Savings Single Nucleotide Polymorphism Structure System Testing Toxic effect Toxicology Variant cancer type cohort drug development electric impedance exome sequencing experimental study exposed human population genome wide association study improved indexing induced pluripotent stem cell innovation insight kinase inhibitor mortality novel novel marker novel therapeutics patient subsets rare variant response targeted cancer therapy

项目摘要

Abstract The development of kinase inhibitors (KIs) has revolutionized the treatment of a broad spectrum of cancer types. However drug-related adverse effects often counter the benefits of anti-cancer drugs. With the widespread use of KIs, it has become apparent that a subset of patients develops cardiac dysfunction and heart failure. Currently our knowledge of the underlying pathophysiology and risk factors is limited. Experiments focusing on understanding the molecular and genetic mechanisms underlying cardiotoxicity will be critical to improve and guide further drug development. The recent development of human induced pluripotent stem cells (hiPSCs) and the ability to differentiate hiPSCs into CMs (hiPSC-CMs) offer unprecedented opportunities for disease modeling and cardiotoxicity testing. Human iPSC-CMs exhibit properties highly similar to their primary counterparts, thus providing a relevant `patient in a dish' model. The overarching goal of this proposal is to identify and understand the molecular and genetic mechanisms underlying KI-induced cardiotoxicity by using hiPSC-CMs. The proposal builds on extensive infrastructure funded through various NHLBI grants. We have generated 250 hiPSCs lines and differentiated these lines into CMs from participants in the NHLBI HyperGEN cohort. We propose to use these hiPSC-CMs to identify underlying pathways and genetic markers, which contribute to the variability in the response to KIs. Using expression analysis, we will describe the distinct molecular responses associated with exposing hiPSC- CMs to KIs. We will perform standard phenotypic analyses, expression analysis and functional assays for cardiotoxicity. Subsequently we will perform pathway expression analysis to identify novel functional networks associated with KI cardiotoxicity. In addition, we will be utilizing previously obtained GWAS and whole exome sequencing data to perform expression quantitative trait locus analysis to determine variants associated with KI-induced cardiotoxicity. Our proposal applies a precision and systems medicine approach to the study of cardiotoxicity. Furthermore the proposed approach can provide important insights for the future development of novel KIs with a reduced cardiotoxic risk profile.

摘要