Acute radiation injury alters microRNA profiles that predict late tissue-specific damage

项目总结 尽管对辐射对正常组织的影响进行了广泛的调查，但目前还没有简单的方法 为了快速确定一个人是否受到过辐射，剂量和类型，以及他们是否有可能 遭受严重的急性或延迟后果。时间也可能是对大量 个人和考虑到这一点，已经为发现和开发 提供引人注目的解决方案的新型生物剂量计；即循环微RNA(MiRNA)剖析。它是 基于我们在研究急性辐射综合征(ARS)幸存者方面的丰富经验 非人灵长类动物模型，以及我们对延迟效应发展道路的理解， 它不遵循与ARS相同的严格的时间-剂量限制。相反，它们显示了常见的模式 炎症和异常的免疫参与，导致晚期组织毒性和过早死亡。我们的 假设辐射诱导的全身性髓系细胞动员和免疫造血失衡 驱动晚期辐射损害，值得注意的是，这种损害只发生在一些小鼠身上，而不发生在其他小鼠身上。我们有令人信服的 有证据表明，辐照组织免疫界面上的动态事件反映在可测量的 循环中的miRNAs图谱表明，它们1)与最初的辐射侮辱密切相关，2) 先于晚期组织特异性辐射诱导的毒性，如心脏和肺的纤维化。 在此背景下，我们建议开发一组miRNAs并建立一个全面的生物标记物 集成急性和晚期辐射损伤信号的平台。我们的目标是扩展我们现有的 来自低LET暴露的知识，并确定已知的miRNA变化模式是否固有 对于不同性质的辐射，如果与之相关的组织损伤性质也会发生变化。在……里面 目标1我们将确定定义辐射诱导组织的广泛参数，如剂量率和时间 X射线与中子暴露造成的造血性急性呼吸窘迫综合征后的损害。我们将依靠 经过验证的、强大的终点，如临床检查、血液检查和尸检等，以及更多的组织 捕捉多器官疾病的特定读数。将为以下对象生成纵向血浆miRNA分布 每只小鼠作为目标2的一部分，并在组织损伤的背景下对齐，以识别假定的生物标记物 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记物小组的候选人 (目标3)。这项研究与急性和慢性辐射影响有广泛的相关性，它是复杂的 辐射损伤组织与免疫稳态的相互作用。我们意识到这些挑战 当使用体内照射和固有的复杂性来比较X射线和中子时会出现这种情况 在研究晚期疾病方面。因此，我们组建了一个结合了辐射生物学专业知识的团队， 免疫学、miRNA图谱、辐射物理和剂量学、兽医护理和统计，以涵盖所有 这项研究的几个方面。

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.