Acute radiation injury alters microRNA profiles that predict late tissue-specific damage

急性辐射损伤改变了预测晚期组织特异性损伤的 microRNA 谱

• 批准号: 10329926
• 负责人: Dorthe Schaue
• 金额: $ 48.77万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 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/10329926
• 关键词: Acute; Address; Age; Animal Model; Animals; Attention; Autopsy; Biological Assay; Biological Markers; Blood; Body Weight; Bone Marrow; Caring; Cessation of life; Characteristics; Chemicals; Chronic; Complex; Cox Proportional Hazards Models; Data; Dependence; Development; Diagnosis; Disease; Dose; Dose-Rate; Echocardiography; Event; Exposure to; Fibrosis; Fright; Gender; Goals; Heart; Hematopoietic; High-LET Radiation; Histology; Homeostasis; Human; Immune; Immune System Diseases; Immune system; Immunology; Inbred C3H Mice; Incidence; Individual; Inflammation; Inflammatory; Infrastructure; Investigation; Ionizing radiation; Kidney; Knowledge; Late Effects; Lead; Liver; Longevity; Lung; Measurable; Medical; MicroRNAs; Mind; Modeling; Monitor; Morbidity - disease rate; Mus; Myeloid Cells; Nature; Neutrons; Normal tissue morphology; Nuclear; Organ; Outcome; Pancreas; Pancreatic enzyme; Pathway interactions; Patients; Pattern; Persons; Plasma; Population; Prognosis; Quantitative Reverse Transcriptase PCR; Radiation; Radiation Accidents; Radiation Dose Unit; Radiation Injuries; Radiation Physics; Radiation Toxicity; Radiation exposure; Radiation induced damage; Radiobiology; Radiometry; Research; Risk; Roentgen Rays; Screening procedure; Signal Transduction; Statistical Data Interpretation; Survivors; System; Terrorism; Time; Tissues; Toxic effect; Triage; Veterinary Medicine; Whole-Body Irradiation; Work; X-Ray Computed Tomography; base; biodosimeter; biological adaptation to stress; biomarker panel; cancer radiation therapy; candidate marker; circulating microRNA; clinical examination; data mining; experience; heart damage; improved; in vivo; irradiation; lung injury; male; miRNA expression profiling; mindfulness; mortality; nonhuman primate; novel; premature; radiation effect; radiation-induced tissue damage; response; statistics

PROJECT SUMMARY Despite extensive investigations into the effects of radiation on normal tissues, there is currently no easy way to quickly determine if a person has been exposed to radiation, to what dose and type, and if they are likely to suffer serious acute or delayed consequences. Time may also be of the essence for triaging large numbers of individuals and with that in mind have developed a robust infrastructure for the discovery and development of a novel biodosimeter that offers a compelling solution; namely circulating microRNA (miRNA) profiling. It is based on our extensive experience in studying survivors of acute radiation syndromes (ARS) in murine and non-human primate models, and our understanding of the road toward the development of delayed effects, which don’t follow the same strict time-dose constraints as ARS. Instead, they display common patterns of inflammation and aberrant immune engagement, leading to late tissue toxicity and premature death. Our hypothesis is that radiation-induced systemic myeloid cell mobilization and immunohematopoietic imbalance drive late radiation damage that, remarkably, occurs only in some mice and not in others. We have compelling evidence that dynamic events at the irradiated tissue-immune interface are reflected in a measurable shift in the circulating miRNAs landscape suggesting that they 1) go hand-in-hand with the initial radiation insult and 2) precede late tissue-specific radiation-induced toxicities such as fibrosis in heart and lung. Against this backdrop we propose to develop a panel of miRNAs and build a comprehensive biomarker platform that integrates signals from both acute and late radiation damage. Our goal is to extend our existing knowledge from low LET exposures and determine if known patterns of miRNA changes are inherently different for radiation of different qualities, and if the nature of the associated tissue damage also changes. In Aim 1 we will determine broad parameters such as dose-rate and time that define radiation-induced tissue damage in the aftermath of hematopoietic ARS caused by X-rays versus neutron exposures. We will rely on proven, robust endpoints such clinical examination, blood work and necropsy amongst other, more tissue specific readouts to capture multi-organ disease. Longitudinal plasma miRNA profiles will be generated for each mouse as part of Aim 2 and aligned within the context of tissue damage to identify putative biomarker candidates to achieve our ultimate goal and build a biomarker panel for tissue- and radiation-specific damage (Aim 3). The study has broad relevance to acute and chronic radiation effects and it epitomizes the complex interaction between radiation-damaged tissues and immune homeostasis. We are mindful of the challenges that arise when comparing X-rays with neutrons using in vivo irradiation and the complexities that are inherent in studying late morbidities. We therefore assembled a team that combines expertise in radiation biology, immunology, miRNA profiling, radiation physics and dosimetry, veterinary care and statistics to cover all aspects of this research.

项目摘要 尽管对辐射对正常组织的影响进行了广泛的研究，但目前没有简单的方法 快速确定一个人是否暴露于辐射，剂量和类型的剂量以及是否可能 遭受严重的急性或延迟后果。时间也可能是大量分类的本质 个人，考虑到这一点，已经为发现和发展一个强大的基础设施建立了一个 提供令人信服的解决方案的新型生物测量表；即循环microRNA（miRNA）分析。这是 根据我们在研究鼠类急性辐射综合征（AR）和 非人类灵长类动物模型，以及我们对发展延迟影响的道路的理解， 与AR相同的严格时间剂量约束。相反，它们显示了常见的模式 炎症和异常免疫接合，导致组织晚期毒性和过早死亡。我们的 假设是辐射诱导的全身性髓样细胞动员和免疫摩托比亚失衡 驱动较晚的辐射损伤，显着地仅在某些小鼠中而不是在其他小鼠中发生。我们很有说服力 证据表明，辐照组织 - 免疫接口处的动态事件反映在可测量的转移中 循环中的miRNA景观表明它们1）与初始辐射损伤并驾齐驱2） 在组织晚期辐射引起的毒性之前，例如心脏和肺中的纤维化。 在此背景下，我们建议开发一个miRNA小组并建立全面的生物标志物 平台集成了急性和晚期辐射损伤的信号。我们的目标是扩展我们的现有 从低点曝光的知识并确定miRNA变化的已知模式是否本质上是固有的 不同质量的辐射以及相关组织损伤的性质也有所不同。在 AIM 1我们将确定广泛的参数，例如定义辐射诱导的组织的剂量率和时间 X射线与中子暴露引起的造血ARS的损害。我们将依靠 经过验证，稳健的终点，例如临床检查，血液检查和尸检等其他组织 特定的读数以捕获多器官疾病。将生成纵向等离子体miRNA轮廓的 每只小鼠作为AIM 2的一部分，并在组织损伤的背景下对齐以识别推定的生物标志物 候选人实现我们的最终目标并建立针对组织和辐射特定损害的生物标志物面板 （目标3）。该研究与急性和慢性辐射效应具有广泛的相关性，并且它体现了复合物 辐射受损的组织与免疫稳态之间的相互作用。我们注意挑战 当使用体内辐照和继承的复杂性比较X射线与中子进行比较时会产生。 在研究晚期病情时。因此，我们组建了一个结合了放射生物学专业知识的团队， 免疫学，miRNA分析，辐射物理学和剂量法，兽医护理和统计数据涵盖所有 这项研究的各个方面。