Identification of Biomarkers for Late Radiation Lung Damage

晚期放射性肺损伤生物标志物的鉴定

基本信息

批准号：
8473782
负责人：
Jacob N Finkelstein
金额：
$ 36.31万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8473782
关键词：
Acute Adult Affect Age Age-Months Animals Biological Markers Bleomycin Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid Caring Chest Child Childhood Chronic Clara cell-specific protein Clinic Collagen Data Development Disease Disease Progression Dose Elderly Endotoxins Etiology Event Exposure to Functional disorder Funding Goals Grant Human Human Resources Inbred C57BL Mice Incidence Inflammation Inflammatory Influenza Injury Intervention Japanese Population Late Effects Light Liquid substance Lung Lung diseases Lymphocyte Measurement Measures Modeling Morbidity - disease rate Mouse Strains Mus Newborn Animals Nuclear Organ Outcome Pattern Persons Plasma Play Population Proteins Pulmonary Fibrosis Pulmonary Surfactant-Associated Protein D Radiation Radiation Injuries Radiation Pneumonitis Radiation Syndromes Radiation Tolerance Radiation therapy Risk Role Sampling Serum Serum Markers Specificity Stream Survivors Syndrome Terrorism Testing Time Tissues Trauma Weaning Whole-Body Irradiation aged biodosimeter comparative indexing irradiation lung injury macrophage mortality mouse model named group neonate prevent pulmonary function radiation effect research study response

项目摘要

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.

描述（由申请人提供）：鉴于当前恐怖主义风险加剧的状况，迫切需要一种易于评估、特性良好且广泛适用的生物剂量计，以便识别那些可能易受恐怖主义相关发病率和死亡率影响的人员。大规模放射性或核事件的肺部后果。事实上，由于我们照顾急性意外（或故意）接触受害者的能力不断增强，接触者更有可能在因全身接触而导致的直接血液危机中幸存下来；然而，晚期发病可能是多器官功能障碍综合征的一部分。因此，肺等器官在该综合征的进展中所发挥的下游作用越来越受到关注，需要确定并及时采取缓解措施。我们相信，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/CC16），它以损伤特异性模式表达，可在血浆中识别。为了充分表征该生物标志物，我们将利用相关的“2-品系”小鼠模型，从而涵盖人类中观察到的肺部终点谱。此外，我们将通过使用新生和老年小鼠模型来评估生物标志物在两个特殊人群（儿童和老年人）中的差异表达模式。三个具体目标包括： 1. 检验以下假设：受辐射动物血浆中 Clara 细胞分泌蛋白（CCSP 或 CC16）量与表面活性剂蛋白-D (SP-D) 表达量的变化将预测发病率和进展放射性纤维化； 2. 测试CCSP的特异性其他肺损伤模型中导致炎症和/或纤维化反应的标志物； 3. 确定 CCSP 作为“特殊”人群慢性肺损伤标志物的效用。此类生物标志物的价值既在于其预测暴露后疾病进展的能力，又在于其在评估可用于预防此类伤害的缓解策略的功效方面的有用性。重要的是，这项工作中寻求的生物标志物是效果标志物，而不是剂量标志物，从而在做出有关潜在干预措施的关键决策之前提供所需的附加信息。我们预计，在资助期结束时，我们将确定 CCSP 的时间和剂量特异性表达模式，CCSP 是一种生物标志物，有可能被开发用于放射事件后的立即和延迟期。