Identification of Biomarkers for Late Radiation Lung Damage

描述（由申请人提供）：鉴于目前恐怖主义风险加剧的状态，迫切需要一种易于评估、特征明确且广泛适用的生物剂量计，以识别那些可能易受与大规模放射性或核事件的肺部后果相关的发病率和死亡率影响的人员。事实上，由于我们照顾急性意外（或故意）暴露受害者的能力增强，暴露者更有可能在全身暴露导致的即时血液学危机中幸存下来；然而，晚期发病可作为多器官功能障碍综合征的一部分发生。因此，肺等器官在该综合征的进展中所起的下游作用越来越受到关注，需要加以确定，以便及时采取缓解措施。我们认为，我们已经确定了辐射诱导的肺晚期效应进展的潜在生物标志物，Clara细胞分泌蛋白（CCSP/CC16），该蛋白以损伤特异性模式表达，可在血浆中识别。为了充分表征这种生物标志物，我们将使用相关的“2株”小鼠模型，从而覆盖在人类群体中看到的肺终点谱。此外，我们将通过使用新生儿和老年小鼠模型来评估两种特殊人群（儿童和老年人）中生物标志物的差异表达模式。三个具体目标包括：1。验证辐照动物血浆Clara细胞分泌蛋白（CCSP或CC16）与表面活性剂蛋白- d （SP-D）表达量的变化预测辐射纤维化的发生和进展的假设；2. 测试CCSP的特异性

DESCRIPTION (provided by applicant): In light of the current state of heightened terrorism risk, an easily assessed, well-characterized and broadly applicable biodosimeter is urgently required in order to identify those personnel that may be susceptible to the morbidity and mortality associated with the pulmonary consequences of a mass radiological or nuclear event. Indeed, due to our increased ability to care for victims of acute accidental (or intentional) exposure, exposed persons are more likely to survive the immediate hematological crises which result from whole body exposure; however late morbidities then can occur as part of a multi-organ dysfunction syndrome. Therefore, the down- stream roles played by such organs as the lung in this syndrome's progression are of increasing concern and need to be identified in order to employ timely mitigation. We believe that we have identified a potential biomarker of radiation-induced lung late effect progression, Clara cell secretory protein (CCSP/CC16), which is expressed in an injury-specific pattern, identifiable in the plasma. In order to fully characterze this biomarker, we will make use of a pertinent "2-strain" murine model, thereby covering the spectrum of lung endpoints seen in the human population. In addition, we will assess the differential expression pattern of the biomarker in two special populations, children and the elderly, through the use of neonate and aged mouse models. The three specific aims include: 1. To test the hypothesis that changes in the amount of Clara cell secretory protein (CCSP or CC16) versus surfactant protein-D (SP-D) expression in the plasma of irradiated animals will predict the incidence and progression of radiation fibrosis; 2. To test the specificity of the CCSP marker in other models of lung injury that result in an inflammatory and/or fibrotic response; 3. To determine the utility of CCSP as a marker of chronic lung injury in a "special" population. The value of such biomarkers exists both in their ability to predict the progression of disease following exposure and their usefulness in evaluating the efficacy of mitigation strategies that may be employed to prevent such injury. Importantly, the biomarkers being sought in this effort are markers of effect, and not markers of dose, thereby providing the additional information required before making critical decisions regarding potential interventions. We anticipate that by the end of the funding period, we will have identified the time- and dose-specific patterns of expression of CCSP, a biomarker that could potentially then be developed for use in both the immediate and delayed periods following a radiological event.