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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要尽管对辐射对正常组织的影响进行了广泛的研究，但目前还没有简单的方法快速确定一个人是否接触过辐射、辐射剂量和类型以及是否可能接触过辐射遭受严重急性或延迟后果的患者，时间对于对大量患者进行分类也至关重要。个人并考虑到这一点，开发了强大的基础设施，用于发现和开发新型生物剂量计提供了引人注目的解决方案；即循环 microRNA (miRNA) 分析。基于我们对小鼠急性辐射综合征 (ARS) 幸存者的丰富研究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，它们不遵循与 ARS 相同的严格时间剂量限制，而是表现出常见的模式。炎症和异常的免疫参与，导致晚期组织毒性和过早死亡。假设是辐射引起的全身骨髓细胞动员和免疫造血失衡导致晚期辐射损伤，这种情况很少见，仅发生在某些小鼠身上，而不会发生在其他小鼠身上。我们有令人信服的证据。有证据表明，受辐射组织-免疫界面的动态事件反映在可测量的变化中循环的 miRNA 景观表明它们 1) 与最初的辐射损伤密切相关，2) 先于晚期组织特异性辐射引起的毒性，例如心脏和肺纤维化。在此背景下，我们建议开发一组 miRNA 并建立一个全面的生物标志物集成来自急性和晚期辐射损伤的信号的平台我们的目标是扩展我们现有的。低 LET 暴露的知识并确定已知的 miRNA 变化模式是否本质上是不同质量的辐射会有所不同，并且相关组织损伤的性质也会发生变化。目标 1 我们将确定定义辐射诱导组织的广泛参数，例如剂量率和时间我们将依赖 X 射线与中子暴露引起的造血 ARS 后的损害。经证实的、稳健的终点，例如临床检查、血液检查和尸检等更多组织将生成用于捕获多器官疾病的纵向血浆 miRNA 谱的特定读数。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对齐，以识别假定的生物标志物候选人实现我们的最终目标并建立组织和辐射特异性损伤的生物标志物组（目标 3）。该研究与急性和慢性辐射效应具有广泛的相关性，并且集中体现了复杂的情况。我们注意到辐射损伤组织与免疫稳态之间的相互作用。使用体内照射比较 X 射线与中子时出现的问题以及固有的复杂性因此，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、辐射物理和剂量测定、兽医护理和统计学涵盖所有内容这项研究的各个方面。