PROJECT SUMMARY Cardiovascular imaging is the cornerstone for the management of complex cardiovascular disease. Due to the rapidly growing reliance on imaging for diagnosis and monitoring, many patients now receive more radiation from medical imaging than ever before, a trend that will likely continue to accelerate. This raises growing concerns about the potential risk from exposure to low-dose radiation from medical imaging. Radiation dose of 10-20 millisieverts (mSv), a measure of radiation exposure, for cardiac computed tomography angiography (CTA) is equivalent to approximately 100-600 chest x-rays and comparable with other diagnostic procedures, although the exact dose differs significantly among study sites and CT systems (5.7 to 36.5 mSv). However, whether this type of common low-dose radiation causes significant cellular damage has not been fully explored, due to a lack of sufficiently large and well-controlled cohorts for epidemiological studies, as well as a lack of experimental tools for assessing responses after low- dose exposure. This is problematic as the biological effects upon exposure to low-dose or high-dose radiation differ significantly; hence this proposal addresses a pressing concern in the biomedical imaging field. I have developed and validated a set of biomarkers for assessing low-dose radiation risks in ex vivo irradiated human blood and in adult patients undergoing different forms of low-dose cardiac imaging procedures, namely single photon emission computed tomography myocardial perfusion imaging (SPECT MPI), invasive coronary angiography, and cardiac CTA. By using a set of proteomic and genomic biomarkers and state-of-the-art techniques such as single cell PCR, protein phosphorylation, and RNA-sequencing, I will determine whether exposure to low-dose radiation from cardiac CTA triggers both proteins and gene changes associated with DNA damage in adult patients. Candidate genes and pathways identified by RNA-sequencing analysis will allow us to elucidate the molecular mechanisms underlying radiation sensitivity, and the use of the individualized patient-specific T-lymphocytes and human induced pluripotent stem cells will predict acute radiation sensitivity in individuals. In this study, CTA is used as a proof-of-concept study as cells are exposed to a single-dose radiation. However, this platform can be extended to various other imaging modalities, including the prediction of cumulative exposure to radiation that will be invaluable for personalized or precision medicine in the future. Finally, such a high-throughput platform can be applied to personalized genomic and proteomic measures of clinical response to radiation therapy, which may lead to the development of novel strategies by avoiding toxicity while maximizing therapeutic efficacy.

PROJECT NARRATIVE This study will fill crucial gaps in our current understanding of the complex overall cellular responses related to the risk of low-dose radiation by utilizing cardiac computed tomographic angiography (CTA) in a proof-of-concept study. Although cardiac CTA is a powerful clinical tool in the diagnosis and treatment of complex cardiovascular disease, growing awareness among physicians that DNA damage and cellular apoptosis can occur even at low doses of radiation exposure recognizes the need for greater adherence to dose reduction strategies and further research to develop novel agents to protect patients from potential adverse effects of low dose radiation exposure from cardiac CTA. In addition, this study aims to demonstrate the use of individualized induced pluripotent stem cells as a model for predicting inter- individual radiosensitivity, which will benefit prospective patients undergoing medical imaging procedures and minimize their exposure risk in clinical practice.