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: 10557205
• 负责人: Dorthe Schaue
• 金额: $ 40.17万
• 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/10557205
• 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; Liver; Longevity; Lung; Measurable; Medical; MicroRNAs; 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 Injuries; Radiation Physics; Radiation Toxicity; Radiation exposure; Radiation induced damage; Radiobiology; Radiometry; Recurrence; 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; 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.

项目总结