Innovative Biomarkers to Predict Radiation Lung Injury

描述(申请人提供)：肺是一个对辐射敏感的器官，在1950至2000年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段很长的时间窗口(6-8周)。我们有证据表明，如果在暴露后35天开始使用缓释剂，可以降低大鼠肺炎的致死率。因此，预测放射性事件后30天内肺损伤的生物标志物将在识别和保护大规模伤亡事件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全胸照射的剂量，以可重复性的方式在0-100%的大鼠中诱导致死性肺炎。使用这样的模型，我们已经测试了超过15种肺功能分析和26种循环蛋白。基于我们和其他人的结果，我们选择了三类微创和新型生物标志物作为预测致死性肺炎的候选指标。我们将使用低(X射线)和混合(中子和伽马射线)线性能量转移(LET)辐射源来测试我们的生物标记物，这些辐射源类似于原子弹。在目标1中，呼气和血液标记物将被测试。呼出气体中一氧化氮(NO)的增加，已被证明可以预测放射性肺炎。血液将被用来识别所有可能预测肺损伤的新的或现有的循环微RNA，使用穷举下一代测序(MicroRNA Seq)方法。目标2将专注于RFA的另一个感兴趣的领域，即器官特异性成像。使用单光子发射计算机断层扫描(SPECT)，我们将对肺部成像，以测量体内肺血流灌注的减少(已知在辐射后以特定模式发生)和/或肺细胞死亡，这可能预测致死性肺炎。在目标3中，我们将在第二种大鼠身上确认来自目标1和目标2的辐射特异性肺损伤的阳性生物标记物。最后，我们将通过在大鼠身上进行盲法试验来预测放射性肺炎并测量所选生物标记物的准确性来证实我们的结果。结合已建立的模型、高通量测序技术和高效的研究设计，将使我们能够及时完成我们的目标。我们已经建立了辐射损伤模型，并建立了一个包括知名专家在内的团队来帮助我们实现我们的目标。

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.