Innovative Biomarkers to Predict Radiation Lung Injury

描述（由申请人提供）：肺是一个对辐射敏感的器官，1950年至2000年期间报告的所有核事故中至少有一半包括肺损伤。与胃肠道、皮肤和血液损伤不同，辐射暴露和肺功能障碍症状之间有一个明显的时间窗口（6-8周）。我们有证据表明，缓解剂可以降低大鼠在接触后35天开始的肺炎致死率。因此，在放射性事件后的前30天内预测肺损伤的生物标志物将在识别和保护大规模伤亡事件的受害者免受肺损伤方面发挥非常重要的作用。我们已经确定了全身和整个胸部照射剂量，诱导致命性肺炎在一个可重复的方式从0- 100%的大鼠。使用这些模型，我们已经测试了超过15种肺功能和26种循环蛋白质的测定。根据我们的研究结果和其他人的研究结果，我们选择了三类微创和新型生物标志物作为预测致命性肺炎的候选物。我们将用类似原子弹的低（X射线）和混合（中子和伽马射线）线性能量转移（LET）辐射源测试我们的生物标志物。在目标1中，将检测呼出气和血液标志物。呼出气中气体一氧化氮（NO）的增加，已被证明是预测放射性肺炎。血液将用于使用详尽的下一代测序（microRNA seq）方法鉴定所有可能预测肺损伤的新的或现有的循环microRNA。目标2将重点关注RFA的另一个感兴趣的领域，器官特异性成像。使用单光子发射计算机断层扫描（SPECT），我们将对肺部进行成像，以测量体内肺灌注的减少（已知在辐射后以特定模式发生）和/或可能预测致命性肺炎的肺细胞死亡。在目标3中，我们将在第二种大鼠中确认目标1和2的放射特异性肺损伤的生物标志物阳性。最后，我们将通过在大鼠中进行盲法试验来预测放射性肺炎并测量所选生物标志物的准确性，从而证实我们的结果。建立的模型，高通量测序技术和有效的研究设计的组合将使我们能够及时完成我们的目标。我们建立了辐射损伤模型，并组建了一支包括知名专家在内的团队，帮助我们实现目标。

DESCRIPTION (provided by applicant): The lung is a radiosensitive organ and at least half of all the nuclear accidents reported between 1950 and 2000 include lung injuries. Unlike gastrointestinal, skin and hematological injuries, there is a significant window of time (6-8 weeks) between radiation exposure and symptoms of pulmonary dysfunction. We have evidence that mitigating agents can reduce lethality from pneumonitis in rats when started as late as 35 days post exposure. Therefore, biomarkers that predict lung injury in the first 30 days after a radiological event will serve a very important role in identifying and protecting victims o a mass casualty event from lung injury. We have identified doses of total body and whole thorax irradiation that induce lethal pneumonitis in a reproducible manner from 0-100 percent of rats. Using such models, we have tested over 15 assays of lung function and 26 circulating proteins. Based on our results and those of others, we have chosen three classes of minimally invasive and novel biomarkers as candidates to predict lethal pneumonitis. We will test our biomarkers with low (X-rays) and mixed (neutrons and gamma rays) linear energy transfer (LET) sources of radiation that resemble an A-bomb. In Aim 1, exhaled breath and blood markers will be tested. Increase in the gas nitric oxide (NO) in exhaled breath, has been demonstrated to predict radiation pneumonitis. Blood will be used to identify all novel or existing circulating microRNA that may predict lung injury, using an exhaustive next-generation sequencing (microRNA seq) approach. Aim 2 will focus on another area of interest of the RFA, organ-specific imaging. Using single-photon emission computed tomography (SPECT) we will image lungs to measure the decrease in pulmonary perfusion in vivo (known to occur in a specific pattern after radiation) and/or pulmonary cell death that may predict lethal pneumonitis. In Aim 3 we will confirm biomarkers positive for radiation-specific lung injury from Aims 1 and 2 in a second species of rat. Finally, we will confirm our results by conducting a blinded trial in rats to predict radiatio pneumonitis and measure the accuracy of the selected biomarkers. A combination of established models, a high throughput sequencing technique and efficient study design will allow us to complete our aims in a timely manner. We have established models of radiation injury and a team which includes renowned experts to help us reach our goals.