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

描述（由申请方提供）：随着全球社会政治局势的变化和具有核弹头能力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（例如之后的核灾难）中的辐射暴露 日本海啸）是当前和未来持续的威胁。这种辐射照射的最重要特点是，对身体不同部位的辐射剂量不均匀，症状的突出程度取决于器官受损的程度，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在受照射后数天、数周和数月出现，这可能导致任何治疗方案的使用延迟。 现有的生物剂量测定技术和装置不能预测特定器官和组织所遭受的损伤的严重程度，因此不能提供任何可用的辐射医疗对策可能提供的及时的针对器官和组织的医疗治疗。我们最近发现，一类新的基因表达调控因子，microRNA（miRNA），影响辐射反应。miRNA是小的（20-22 nt），非常稳定的分子，易于在各种组织和体液（包括血清）中回收和检测。正在探索使用血清miRNA表达模式作为包括外部创伤在内的不同病理状况的预测标志物。与大量的mRNA不同，人类基因组中只有约1400种miRNA，并且适度数量的miRNA可能足以区分对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）引起小鼠造血损伤，并在损伤后一天和一周评估血清miRNA谱。 组织学和细胞分析显示，特定的血清miRNAs与辐射诱导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miRNAs组可以让我们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。为了评估血清miRNA谱随肺损伤的变化，我们对胸部区域使用多剂量的局部辐射，并在暴露后数周检查血清miRNA谱。有特定的血清miRNAs组，对应于辐射诱导的肺损伤的剂量依赖性的方式。这些结果表明，血清miRNA表达可能作为一种新的生物标志物的急性和迟发性辐射损伤的造血系统和肺。总的来说，我们的目标是建立在我们的初步研究和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.