Serum microRNA as biomarker for radiation injury to lung and hematopoietic cells

血清 microRNA 作为肺和造血细胞辐射损伤的生物标志物

• 批准号: 9064076
• 负责人: Dipanjan Chowdhury
• 金额: $ 42.23万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9064076
• 关键词: Acute; Affect; Age; Animals; Appearance; Applications Grants; Biological Assay; Biological Markers; Body Fluids; Body part; Bone Marrow; Breathing; Cells; Characteristics; Chest; Clinical; Complex; Cytogenetic Analysis; Data; Devices; Disasters; Dose; Event; Exogenous Factors; Exposure to; Foundations; Future; Gene Expression; Global Change; Goals; Health; Hematopoietic; Hematopoietic System; Heterogeneity; Human Genome; In Vitro; Individual; Industrial Accidents; Infection; Injury; Interleukin-3; Intrinsic factor; Japan; Kinetics; Lead; Lung; Lymphocyte Depletion; Measures; Mediating; Medical; Messenger RNA; MicroRNAs; Modeling; Mouse Strains; Mus; Natural Disasters; Nuclear; Nuclear Weapon; Organ; Pattern; Physiological; Plants; Population; Population Heterogeneity; Procedures; Public Health; Radiation; Radiation Injuries; Radiation induced damage; Radiation therapy; Radioactive; Role; Sepsis; Serum; Severities; Symptoms; System; Techniques; Terrorism; Therapeutic Intervention; Time; Tissues; Trauma; Treatment Efficacy; Triage; Tsunami; Whole-Body Irradiation; base; biodosimetry; cigarette smoking; cost; dirty bomb; effective therapy; exposed human population; in vivo; irradiation; lung injury; mouse model; novel marker; particle; predictive marker; radiation response; radiation-induced injury; response; sex

DESCRIPTION (provided by applicant): The threat of 'dirty bombs' and the possibility of the use of improvised nuclear weapons is growing with the changing global socio-political scenario and politically turbulent situation in nuclear warhead capable states. Hence, radiation exposure in terrorist events, industrial accidents or natural disasters (such as the nuclear disaster after the tsunami in Japan) is a current and continuing threat for the future. The most important characteristic of such radiation exposure is the heterogeneity of the dose delivered to different parts of the body, and the prominence of symptoms depends on the magnitude of damage to the organs resulting in complex patho-physiological features. It is well established that clinical symptoms of radiation injury to different organs and tissues can appear days, weeks and months after exposure, and this could lead to a delay in the use of any treatment options. Existing biodosimetry techniques and devices do not predict the severity of injury sustained by specific organs and tissues, and thus do not allow for the prompt organ- and tissue-directed medical treatment that might be provided by any available radiation medical countermeasures. We have recently discovered that a new class of gene expression regulators, microRNA (miRNA), impact the radiation response. miRNAs are small (20-22 nts), extremely stable molecules that are easily recovered and detected in a variety of tissues and body fluids including blood serum. The use of serum miRNA expression pattern as predictive markers for different pathological conditions including external trauma is being explored. Unlike the vast number of mRNAs, there are only ~1400 miRNAs in the human genome, and a modest number of miRNAs may be sufficient to distinguish injury to specific organs or tissue. Therefore we speculated that serum miRNA profiles may serve as effective biomarkers for predicting radiation damage to hematopoietic system and lung. In preliminary studies we used a sub-lethal dose of total body irradiation (TBI) to cause hematopoietic injury in mice and assessed the serum miRNA profile a day and week after injury. Histopathological and cellular analysis revealed that specific serum miRNAs correlated with radiation induced damage to bone marrow and other aspects of the hematopoietic system. Interestingly, the results also suggested that distinct sets of miRNAs may allow us to estimate the time-frame after radiation exposure (that is days versus weeks), and this in itself could be of importance for the treatment of the exposed individual. To assess serum miRNA profile changes with lung injury we used multiple doses of localized radiation to the thoracic region and examined the serum miRNA profile weeks after exposure. There were specific sets of serum miRNAs that corresponded to radiation-induced lung injury in a dose-dependent manner. These results suggest that serum miRNA expression may serve as a novel biomarker for acute and delayed radiation injury to the hematopoietic system and lung. Overall the goal is to build on our preliminary studies and establish miRNA signatures that predict radiation injury to allow for timely and appropriate treatment of radiation victims.

描述（由申请人提供）：随着全球社会政治形势的变化和拥有核弹头国家的政治动荡局势，“脏弹”的威胁和使用简易核武器的可能性正在增加。 因此，恐怖事件、工业事故或自然灾害（例如核灾难后）中的辐射暴露 日本海啸）是当前和未来持续的威胁。这种辐射暴露最重要的特征是身体不同部位的剂量不均匀，症状的严重程度取决于器官损伤的程度，从而导致复杂的病理生理特征。众所周知，临床 不同器官和组织的辐射损伤症状可能会在暴露后几天、几周和几个月出现，这可能会导致延迟使用任何治疗方案。 现有的生物剂量测定技术和设备不能预测特定器官和组织所遭受的损伤的严重程度，因此不允许任何可用的辐射医疗对策可能提供的迅速的器官和组织定向医疗。我们最近发现一类新的基因表达调节因子，microRNA (miRNA)，会影响辐射反应。 miRNA 是小（20-22 nt）、极其稳定的分子，很容易在各种组织和体液（包括血清）中回收和检测。正在探索使用血清 miRNA 表达模式作为不同病理状况（包括外部创伤）的预测标记。与大量的 mRNA 不同，人类基因组中只有约 1400 个 miRNA，少量的 miRNA 可能足以区分特定器官或组织的损伤。因此我们推测血清miRNA谱可能作为预测造血系统和肺部辐射损伤的有效生物标志物。在初步研究中，我们使用亚致死剂量的全身照射 (TBI) 来引起小鼠造血损伤，并在损伤后一天和一周评估血清 miRNA 谱。 组织病理学和细胞分析表明，特定的血清 miRNA 与辐射引起的骨髓和造血系统其他方面的损伤相关。有趣的是，结果还表明，不同的 miRNA 组可能使我们能够估计辐射暴露后的时间范围（即几天与几周），这本身对于暴露个体的治疗可能很重要。为了评估肺损伤时血清 miRNA 谱的变化，我们对胸部区域使用了多剂量的局部辐射，并在暴露几周后检查了血清 miRNA 谱。有一组特定的血清 miRNA 以剂量依赖性方式与辐射引起的肺损伤相对应。这些结果表明，血清 miRNA 表达可能作为造血系统和肺部急性和迟发性放射损伤的新型生物标志物。总体而言，我们的目标是在我们的初步研究的基础上建立预测辐射损伤的 miRNA 特征，以便及时、适当地治疗辐射 受害者。