Elucidating Sex Differences in Radiation-induced Cardiotoxicity with Cell Village iPSCs

Project Summary Radiation-Induced Cardiotoxicity (RIC) remains a concerning health issue, particularly in accidental radiation exposure scenarios as evident in the Life Span Study of Japanese atomic bomb survivors. However, the complex interplay of factors contributing to the diverse presentations of RIC remains elusive. This project aims to shed light on the critical roles of sex hormone “estrogen” and genetic variations in estrogen receptor (ER) signaling in modulating RIC susceptibility and response. The research takes an innovative approach by combining state-of- the-art techniques and multidisciplinary expertise. Firstly, a "cell village" strategy will be employed which leverage pooling human induced pluripotent stem cell (iPSC) derivatives from a diverse cohort of 200 individuals. Pooled iPSCs will be differentiated into 3D cardiac organoids (iPSC-COs) and treated with varying doses of estrogen and radiation to simulate different physiological conditions and radiation exposure, respectively. Cutting-edge single-cell genomics and computational technologies will be employed to scrutinize the resulting transcriptomic and epigenomic changes in each individual. This will help us identify inter-individual variations and underlying genetic mutations that contribute to differential molecular responses upon irradiation. Additionally, animal models will be employed to simulate radiological incidences and corroborate multi-omics data to functional outcomes in whole organisms. Collectively, these experiments will elucidate the genes responsible for sexual disparity in RIC and its relation to estrogen signaling which can provide insights into personalized risk prediction and intervention strategies, addressing a critical knowledge gap in the field of radiation biology and cardiovascular health.