Assessment of Low-Dose Radiation Risk and Mechanisms of Individual Radiosensitivity

项目摘要 心血管成像是复杂心血管疾病管理的基石。由于 由于对成像诊断和监测的依赖迅速增长，许多患者现在接受更多 医学成像产生的辐射比以往任何时候都多，这一趋势可能会继续加速。这就提出 人们越来越担心医疗成像中低剂量辐射的潜在风险。 10-20毫西弗（mSv）的辐射剂量，辐射暴露的一种衡量标准，用于心脏计算机 断层扫描血管造影（CTA）相当于约100-600次胸部X线检查， 与其他诊断程序，虽然确切的剂量显着不同的研究中心和CT 系统（5.7至36.5 mSv）。然而，这种常见的低剂量辐射是否会导致显著的 由于缺乏足够大且控制良好的队列，细胞损伤尚未得到充分研究 流行病学研究，以及缺乏实验工具来评估低- 剂量暴露。这是有问题的，因为暴露于低剂量或高剂量时的生物效应 辐射差异显着;因此，该提案解决了生物医学成像中的一个紧迫问题 领域我已经开发并验证了一套生物标志物，用于评估体外低剂量辐射风险 接受不同形式低剂量心脏成像的受辐照人体血液和成人患者 程序，即单光子发射计算机断层扫描心肌灌注成像 （SPECT MPI）、有创冠状动脉造影和心脏CTA。通过使用一组蛋白质组学和 基因组生物标志物和最先进的技术如单细胞PCR，蛋白磷酸化， 和RNA测序，我将确定是否暴露于心脏CTA的低剂量辐射触发 与成人患者DNA损伤相关的蛋白质和基因变化。候选基因和 通过RNA测序分析确定的途径将使我们能够阐明分子机制 潜在的辐射敏感性，以及个体化患者特异性T淋巴细胞的使用， 人类诱导多能干细胞将预测个体的急性辐射敏感性。在本研究中， CTA用作概念验证研究，因为细胞暴露于单剂量辐射。但这 该平台可以扩展到各种其他成像模式，包括预测累积的 暴露于辐射，这将是非常宝贵的个性化或精确医学在未来。最后， 这样的高通量平台可以应用于个性化的基因组和蛋白质组测量， 对放射治疗的临床反应，这可能导致通过避免 毒性，同时最大化治疗效果。

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.