Astronauts on long space missions are exposed to prolonged space radiation exposure which contains highly penetrable ionizing radiation and can cause serious cardiovascular complications. There are many uncertainties in assessing the biological effects of chronic space radiation exposure because space radiation is very distinct from terrestrial radiation such as X-rays or gamma rays. This is especially true when one is exposed to radiation at low dose. Currently, there are no effective countermeasures to prevent or treat space radiation induced health complications.

The objective of this postdoctoral fellowship proposal is to develop novel and effective countermeasure against space radiation induced cardiovascular injury using induced pluripotent stem cells (iPSC). The invention of iPSCs has provided us an accessible, versatile, and adaptable source of stem cells which can be differentiated into any cell types we desire. I will generate cardiomyocytes from iPSCs and screen large number of chemical compounds for radioprotective drugs that preserve the contractility in iPSC cardiomyocytes under mitochondrial stress. Emerging evidence suggests that spaceflight environment causes mitochondrial dysfunction and mitochondrial stress response pathways that contribute to degenerative effects by radiation exposure. Once I identify candidate drugs, I will test them in heart-like organs which are engineered by mixing iPSC-derived cardiomyocytes, endothelial cells, and cardiac fibroblasts. In addition, 3D iPSC-derived engineered heart tissues will undergo chronic space radiation at low dose, and I will comprehensively characterize the functional and molecular changes occurring in engineered heart tissues after irradiation. I will use X-rays as a terrestrial control.

Successful completion of this postdoctoral fellowship study will provide (i) study results of chronic space radiation exposure on human hearts and (ii) development of novel radioprotective countermeasure against space radiation-induced injuries. Reducing uncertainties in cardiovascular risks against space radiation will accelerate humanity’s dream to travel space.

iPSC-CMs from three different donors (comparable to astronaut demographics = Caucasian, male, 30s) were exposed to the different dose or X-rays radiation (0, 2, 5, 10 Gy) and various molecular parameters (viability, DNA-damage, oxidative stress, mitochondrial function) were measured at different times post irradiation (1 hour, 1 day, 3 day) and correlated the functional changes (beating rate, contraction velocity, relaxation velocity) at 14 days post irradiation. Prevailing mitochondrial dysfunction was observed at 3 days post irradiation and co-treatment with antioxidant significantly restored mitochondrial function in irradiated iPSC-CMs. Using oxidative stress as a primary screening parameter, we identified genistein or simvastatin robustly reversed reactive oxygen species (ROS) accumulation in iPSC-CMs following irradiation.

We will further validate the efficacy of genistein and/or simvastatin on advanced 3D culture system (engineered heart tissues) or in a mouse model of radiation induced heart disease in upcoming 2022-2023 TRISH year. A successful completion of this postdoctoral fellowship study will provide (i) study results of chronic space radiation exposure on human hearts and (ii) development of novel radioprotective countermeasure against space radiation-induced injuries. Reducing uncertainties in cardiovascular risks against space radiation will accelerate a humanity’s dream to travel space.

Astronauts on long space missions are exposed to prolonged space radiation exposure which contains highly penetrable ionizing radiation and can cause serious cardiovascular complications. There are many uncertainties in assessing the biological effects of chronic space radiation exposure because space radiation is very distinct from terrestrial radiation such as X-rays or gamma rays. This is especially true when one is exposed to radiation at low dose. Currently, there are no effective countermeasures to prevent or treat space radiation induced health complications.

The objective of this postdoctoral fellowship proposal is to develop novel and effective countermeasure against space radiation induced cardiovascular injury using induced pluripotent stem cells (iPSC). The invention of iPSCs has provided us an accessible, versatile, and adaptable source of stem cells which can be differentiated into any cell types we desire. I will generate cardiomyocytes from iPSCs and screen large number of chemical compounds for radioprotective drugs that preserve the contractility in iPSC cardiomyocytes under mitochondrial stress. Emerging evidence suggests that spaceflight environment causes mitochondrial dysfunction and mitochondrial stress response pathways that contribute to degenerative effects by radiation exposure. Once I identify candidate drugs, I will test them in heart-like organs which are engineered by mixing iPSC-derived cardiomyocytes, endothelial cells, and cardiac fibroblasts. In addition, 3D iPSC-derived engineered heart tissues will undergo chronic space radiation at low dose, and I will comprehensively characterize the functional and molecular changes occurring in engineered heart tissues after irradiation. I will use X-rays as a terrestrial control.

Successful completion of this postdoctoral fellowship study will provide (i) study results of chronic space radiation exposure on human hearts and (ii) development of novel radioprotective countermeasure against space radiation-induced injuries. Reducing uncertainties in cardiovascular risks against space radiation will accelerate humanity’s dream to travel space.