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: 10088403
• 负责人: Dorthe Schaue
• 金额: $ 66.14万
• 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/10088403
• 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调查，但目前还没有简单的方法 快速确定一个人是否暴露在辐射中，辐射的剂量和类型，以及他们是否可能 造成严重的急性或延迟后果。时间也可能是对大量的 个人，并铭记这一点，已经开发了一个强大的基础设施，用于发现和开发一个 新型生物剂量计提供了一个令人信服的解决方案;即循环microRNA（miRNA）谱。是 基于我们在研究小鼠急性放射综合征（ARS）幸存者方面的丰富经验， 非人类灵长类动物模型，以及我们对延迟效应发展之路的理解， 它不像ARS那样遵循严格的时间-剂量限制。相反，它们显示出 炎症和异常免疫参与，导致晚期组织毒性和过早死亡。我们 假设辐射诱导系统性骨髓细胞动员和免疫造血失衡 很明显，这种辐射损伤只发生在一些小鼠身上，而在另一些小鼠身上则没有。我们有令人信服 有证据表明，辐照组织-免疫界面处的动态事件反映在以下可测量的变化中： 循环中的miRNAs景观表明它们1）与初始辐射损伤密切相关，2） 在晚期组织特异性辐射诱导的毒性，如心脏和肺纤维化之前。 在此背景下，我们建议开发一组miRNAs，并建立一个全面的生物标志物 该平台整合了急性和晚期辐射损伤的信号。我们的目标是扩大我们现有的 低LET暴露的知识，并确定已知的miRNA变化模式是否固有地 对于不同质量的辐射，以及如果相关组织损伤的性质也改变，则不同。在 目标1我们将确定广泛的参数，如剂量率和时间，确定辐射诱导组织 X射线与中子照射引起的造血ARS后的损伤。我们将依靠 经过验证的可靠终点，如临床检查、血液检查和尸检，以及其他更多组织检查 特定读数以捕获多器官疾病。将生成纵向血浆miRNA谱， 每只小鼠作为目标2的一部分，并在组织损伤的背景下进行比对，以鉴定推定的生物标志物 候选人，以实现我们的最终目标，并建立一个生物标志物面板组织和辐射特异性损伤 (Aim 3）。这项研究与急性和慢性辐射效应有广泛的相关性，它集中体现了复杂的 辐射损伤组织与免疫稳态之间的相互作用。我们注意到挑战 当比较X射线和中子使用体内照射时， 研究晚期发病率因此，我们组建了一个团队，结合了放射生物学的专业知识， 免疫学、miRNA分析、辐射物理学和剂量学、兽医护理和统计学， 这项研究的各个方面。