Modeling Susceptibility to Radiation Therapy-induced Cardiotoxicity Using Cell Village iPSCs

Project Summary Radiation therapy (RT) is an important component of cancer treatments, yet its usage has been hampered due to cardiovascular side effects. Although RT-induced heart disease (RIHD) disproportionally affects cancer patients, the mechanisms underlying RIHD susceptibility remains elusive. In this multi-PI R01 grant, our team will elucidate the mechanisms underlying RIHD susceptibility by utilizing human induced pluripotent stem cell (iPSC) technology and comprehensive multi-omics profiling of heart tissues after irradiation. We will identify genetic polymorphisms associated with RIHD by mapping expression quantitative trait loci (eQTL) in endothelial cells derived from 250 genetically diverse donors (200 cancer patients and 50 healthy control) after irradiation using single cell RNA-sequencing (Aim 1). We will construct multi-cellular iPSC-derived engineered heart tissues (EHTs) and use complementary genetic mouse model of RIHD for in-depth functional and molecular profiling after irradiation. We will also use cutting-edge multi-omics techniques (transcriptome-epigenome-proteome) to elucidate the molecular signatures underlying RIHD (Aim 2). Finally, we will screen 5,000 FDA approved drugs for mitigating RIHD using novel iPSC reporter constructs for high throughput analysis (Aim 3). In summary, understanding genetic risk factors of adverse tissue response to irradiation and identifying potential radioprotective therapeutics will improve the therapeutic index of RT and minimize RIHD.