Identification of Biomarkers for Late Radiation Lung Damage

描述（由申请方提供）：鉴于目前恐怖主义风险加剧的状况，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，以确定可能易受大规模放射性或核事件肺部后果相关发病率和死亡率影响的人员。事实上，由于我们对急性意外（或故意）暴露受害者的护理能力提高，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，晚期发病率可能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，需要确定以及时缓解。我们认为，我们已经确定了辐射诱导的肺迟发效应进展的潜在生物标志物，克拉拉细胞分泌蛋白（CCSP/CC 16），它以损伤特异性模式表达，在血浆中可识别。为了充分表征该生物标志物，我们将使用相关的“2株”鼠模型，从而涵盖在人群中观察到的肺终点谱。此外，我们将通过使用新生儿和老年小鼠模型评估两个特殊人群（儿童和老年人）中生物标志物的差异表达模式。这三个具体目标包括：1.验证辐射动物血浆中Clara细胞分泌蛋白（CCSP或CC 16）与表面活性蛋白-D（SP-D）表达量的变化可预测辐射纤维化的发生和进展的假设; 2.检测CCSP的特异性 导致炎症和/或纤维化反应的其他肺损伤模型中的标志物; 3.确定CCSP作为“特殊”人群慢性肺损伤标志物的实用性。这些生物标志物的价值在于它们预测暴露后疾病进展的能力以及它们在评估可用于预防这种损伤的缓解策略的功效方面的有用性。重要的是，在这项工作中寻找的生物标志物是效果标志物，而不是剂量标志物，从而在做出关于潜在干预措施的关键决定之前提供所需的额外信息。我们预计，到资助期结束时，我们将确定CCSP表达的时间和剂量特异性模式，CCSP是一种生物标志物，可能随后被开发用于放射性事件后的即刻和延迟期。

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.