Identification of Biomarkers for Late Radiation Lung Damage

晚期放射性肺损伤生物标志物的鉴定

• 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
• 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

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）：鉴于恐怖主义风险的当前状态，迫切需要评估，特征良好的和广泛适用的生物测量表，以确定那些可能易受与大规模散热或核事件的肺部后果相关的发病率和死亡率的人员。确实，由于我们增加了照顾急性意外（或故意）暴露的受害者的能力，因此暴露的人更有可能在全身暴露造成的直接血液学危机中生存；但是，后期的病毒可能会作为多器官功能障碍综合征的一部分。因此，该综合症进展中肺部诸如肺部诸如肺部扮演的沿流角色越来越关注，需要确定需要及时缓解。我们认为，我们已经确定了辐射诱导的肺后期效应进展的潜在生物标志物Clara细胞分泌蛋白（CCSP/CC16），该蛋白在血浆中以损伤特异性模式表达。为了使这种生物标志物充分形象，我们将利用相关的“ 2型”鼠模型，从而涵盖人口中看到的肺端点的范围。此外，我们将通过使用新生儿和老化的小鼠模型来评估两个特殊人群中生物标志物的差异表达模式。这三个具体目的包括：1。检验以下假设：辐照动物血浆中Clara细胞分泌蛋白（CCSP或CC16）与表面活性剂蛋白-D（SP-D）表达的变化将预测辐射纤维化的发生率和进展； 2。测试CCSP的特异性 其他肺损伤模型中的标记，导致炎症和/或纤维化反应； 3。确定CCSP作为“特殊”人群中慢性肺损伤标志的效用。这种生物标志物的价值既存在于预测暴露后疾病进展的能力，又是其在评估可用于防止这种伤害的缓解策略疗效方面的有用性。重要的是，在这项工作中寻求的生物标志物是效果的标志，而不是剂量标记，因此在做出有关潜在干预措施的重要决定之前提供了所需的其他信息。我们预计，在资金期结束时，我们将确定CCSP表达的时间和剂量特异性模式，CCSP的表达方式是一种生物标志物，可以在放射学事件后的直接和延迟期内开发出来，以供使用。