Development of a minimally invasive biomarker assay to detect delayed radiation injury

开发微创生物标志物检测来检测迟发性辐射损伤

• 批准号: 10728721
• 负责人: Marjan Boerma
• 金额: $ 9.97万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728721
• 关键词: Acute; Adolescent; Adult; Age; Animal Model; Animals; Arkansas; Biological Assay; Biological Markers; Blood Urea Nitrogen; Breeding; Childhood; Collaborations; Creatinine; Development; Dose; Early identification; Euthanasia; Exposure to; FDA approved; Female; Fibrosis; Funding; General Population; Goals; Grant; Heart; Heart Injuries; Inbreeding; Individual; Injury; Injury to Kidney; Ionizing radiation; Kidney; Knowledge; Late Radiation Injury; Leg; Lung; Mass Spectrum Analysis; Measures; Medical; Modeling; Monitor; Myocardial dysfunction; National Institute of Allergy and Infectious Disease; Neuropathy; Normal tissue morphology; Nuclear; Nuclear Warfare; Organ; Parents; Pegfilgrastim; Plasma; Population; Proteins; Radiation; Radiation Accidents; Radiation Dose Unit; Radiation Injuries; Radiation Pneumonitis; Radiation Toxicity; Radiation emergency; Radiation exposure; Rat Strains; Rattus; Reporting; Research; Research Design; Resolution; Risk; Roentgen Rays; Sampling; Science; Severities; Stains; Subgroup; System; Technology; Terrorism; Testing; Time; Universities; Urine; Wisconsin; Work; biomarker identification; biomarker panel; biomarker validation; body system; cohort; early detection biomarkers; experience; follow-up; irradiation; juvenile animal; kidney dysfunction; lipidomics; lung development; male; mass casualty; medical countermeasure; medical schools; metabolomics; minimally invasive; organ injury; parent project; personalized management; predictive marker; predictive panel; predictive test; predictive tools; radiation countermeasure; radiation-induced lung injury; response; subcutaneous; validation studies

PROJECT SUMMARY/ABSTRACT The general population continues to be at risk of exposure to ionizing radiation because of nuclear warfare, terrorism, or radiological accidents. Some countermeasures of the acute radiation syndrome (ARS) have been placed in the national stockpile, increasing the chance of survival in a radiation emergency. However, individuals who survive the ARS may develop delayed effects of acute radiation exposure (DEARE) within months to years after irradiation. Currently, no system is available for the early identification of individuals who are at risk for DEARE and in which particular organ systems late radiation injuries will occur. Therefore, to personalize the clinical management of radiation victims, research is required to develop minimally invasive assays that predict organ-specific DEARE. However, although ~25% of the total population is pediatric, to our knowledge, no research has been performed in predictive biomarker assays of DEARE in victims who have been exposed at a young age. The main goal of the NIAID funded grant U01 AI148308 “Development of a minimally invasive biomarker assay to detect delayed radiation injury” is to develop urine and plasma biomarker assays of radiation injury to major organ systems at risk. In this parent project, the initial identification of urine and plasma biomarkers is performed with untargeted high-resolution mass spectrometry-based metabolomics in adult male and female WAG/RijCmcr rats (11-12 weeks of age) exposed to X-rays (0, 6, 9.5 and 13 Gy) with one hind-leg shielded from radiation to assure long-term survival of the animals. In years 1 and 2 of the parent U01 grant, we received supplements to perform studies in a juvenile rat model of leg-out X-ray exposure, to identify early biomarker panels that predict the development of lung, kidney and heart radiation injury. We exposed 41-44 days old male and female WAG/RijCmcr rats to a single dose of 12 Gy, 13 Gy (males), or 13.5 Gy (females). These radiation exposures resulted in radiation pneumonitis and kidney dysfunction within the first 160 days after irradiation. However, long-term kidney and heart injury could not be studied. Therefore, in this supplement application, we propose to expose female WAG/RijCmcr rats at the age of 41-44 days to 9.5 Gy leg-out X-rays. Based on our experience with adult rats, we expect that all animals will survive long-term, which will allow us to examine both kidney and cardiac dysfunction. This radiation dose will then complete a dose response study of DEARE in our juvenile rat model. Moreover, we propose to treat a subcohort of rats with the FDA-approved radiation countermeasure Neulasta, to examine its effects on DEARE as well as predictive biomarkers. We will use the same rat strain and metabolomics/lipidomics approaches as in the parent U01, which will enable us to make comparisons of biomarker panels in juvenile and adult rats.

项目总结/摘要 由于核战争，普通民众继续面临电离辐射的风险， 恐怖主义或放射性事故。介绍了急性放射综合征（ARS）的一些防治措施 储存在国家储备中，增加了在辐射紧急情况下的生存机会。然而，个人 在ARS中存活的患者可能在数月至数年内出现急性辐射暴露（DEARE）的延迟效应 照射后目前，没有系统可用于早期识别有风险的个人， 并在特定的器官系统中发生晚期辐射损伤。因此，要个性化 放射受害者的临床管理，需要研究开发微创检测， 器官特异性DEARE。然而，尽管总人口的~25%是儿科，据我们所知， 研究已经在DEARE的预测生物标志物测定中进行，这些生物标志物测定是在 年纪轻轻NIAID资助的赠款U 01 AI 148308的主要目标是“开发微创 检测迟发性辐射损伤的生物标志物测定”是发展放射性损伤的尿和血浆生物标志物测定 对主要器官系统的伤害有风险。在这个母项目中，尿液和血浆生物标志物的初步鉴定 在成年男性和女性中使用基于非靶向高分辨率质谱的代谢组学 WAG/RijCmcr大鼠（11-12周龄）暴露于X射线（0、6、9.5和13戈伊），一条后腿被屏蔽， 辐射，以确保动物的长期生存。在第1年和第2年的母U 01赠款，我们收到了 补充剂，用于在腿部暴露X射线的幼年大鼠模型中进行研究，以识别早期生物标志物 预测肺、肾和心脏辐射损伤发展的面板。我们将41-44天大的雄性 和雌性WAG/RijCmcr大鼠给予12戈伊、13戈伊（雄性）或13.5戈伊（雌性）的单次剂量。这些辐射 在照射后的头160天内，照射导致放射性肺炎和肾功能障碍。 然而，无法研究长期的肾脏和心脏损伤。因此，在本补充申请中，我们 建议将41-44日龄的雌性WAG/RijCmcr大鼠暴露于9.5戈伊腿部X射线。基于我们 根据成年大鼠的经验，我们预计所有动物都能长期存活，这将使我们能够检查 肾脏和心脏功能障碍。然后，该辐射剂量将完成我们的DEARE剂量反应研究。 幼年大鼠模型。此外，我们建议用FDA批准的放射线治疗大鼠亚组， Neulasta，以检查其对DEARE以及预测生物标志物的影响。我们将使用 与亲本U 01相同的大鼠品系和代谢组学/脂质组学方法，这将使我们能够 幼龄和成年大鼠中生物标志物组的比较。