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

描述(申请人提供)：随着全球社会政治形势的变化和具有核弹头能力的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，在恐怖事件、工业事故或自然灾害(如核灾难后)中暴露的辐射 日本的海啸)是当前和未来的持续威胁。这种辐射照射最重要的特点是照射到身体不同部位的剂量是不同的，症状的突出程度取决于对器官的损害程度，从而导致复杂的病理生理特征。众所周知，临床上 不同器官和组织的辐射损伤症状可能在暴露后几天、几周或几个月出现，这可能导致任何治疗方案的使用延迟。现有的生物剂量学技术和设备不能预测特定器官和组织所受伤害的严重程度，因此不能提供任何可用的放射医学对策可能提供的针对器官和组织的及时医疗。我们最近发现了一类新的基因表达调控因子--microRNA(MiRNA)，它影响辐射反应。MiRNAs是一种小分子(20-22nts)，非常稳定，很容易回收，并在包括血清在内的各种组织和体液中检测到。目前正在探索使用血清miRNA表达模式作为包括外部创伤在内的不同病理条件的预测标记物。与大量的mRNAs不同，人类基因组中只有~1400个miRNAs，少量的miRNAs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谱可作为预测辐射对造血系统和肺的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)造成小鼠造血损伤，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显示，特定的血清miRNAs与辐射引起的骨髓和其他方面的造血系统损伤有关。有趣的是，结果还表明，不同的miRNAs组可能允许我们估计辐射暴露后的时间框架(即几天与几周)，这本身可能对受辐射个人的治疗具有重要意义。为了评估肺损伤时血清miRNA谱的变化，我们对胸部进行了多次局部照射，并在照射后几周检测了血清miRNA谱。有几组特定的血清miRNAs以剂量依赖的方式对应于辐射诱导的肺损伤。这些结果表明，血清miRNA的表达可作为急性和迟发性辐射对造血系统和肺损伤的一种新的生物标志物。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签名，以便及时和适当地治疗辐射 受害者。

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.