Identification of Biomarkers for Late Radiation Lung Damage

说明(申请人提供)：鉴于恐怖主义风险增加的现状，迫切需要一种易于评估、特征良好和适用范围广的生物剂量计，以确定哪些人员可能易受与大规模放射性或核事件的肺部后果有关的发病率和死亡率的影响。事实上，由于我们提高了照顾急性意外(或故意)接触的受害者的能力，接触者更有可能在全身暴露引起的直接血液危机中幸存下来；然而，晚期发病率可能会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发展过程中所起的下游作用日益受到关注，需要加以确定，以便及时缓解。我们认为我们已经确定了一个潜在的辐射诱导的肺迟发效应进展的生物标志物，Clara细胞分泌蛋白(CCSP/CC16)，它以一种损伤特异性的模式表达，可在血浆中识别。为了充分描述这一生物标志物，我们将利用相关的“2株”小鼠模型，从而覆盖在人类群体中看到的肺终点的光谱。此外，我们将通过使用新生和老年小鼠模型来评估该生物标记物在儿童和老年人这两个特殊人群中的差异表达模式。这三个具体目标包括：1.检验辐射动物血浆中Clara细胞分泌蛋白(CCSP或CC16)与表面活性蛋白-D(SP-D)表达的变化将预测放射性纤维化的发生和进展的假设；2.检验CCSP的特异性 在导致炎症和/或纤维化反应的其他肺损伤模型中的标记物；3.确定CCSP在“特殊”人群中作为慢性肺损伤标记物的实用性。这些生物标志物的价值既在于它们能够预测暴露后的疾病发展，也在于它们在评估可用于预防此类伤害的缓解策略的有效性方面。重要的是，在这项工作中寻找的生物标记物是效果的标记物，而不是剂量的标记物，因此在就潜在的干预措施做出关键决定之前提供了所需的额外信息。我们预计，在资金阶段结束时，我们将确定CCSP的时间和剂量特定的表达模式，这是一种生物标记物，随后可能被开发用于放射事件后的即时和延迟期。

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.