急性核辐射损伤与检测技术的基础研究

Accurate medical assessment and dosimetry estimation early triage is vital for for treatment of a large number of wounded people under a nuclear radiation accident. Our preliminary studies have found that acute radiation injury leads to serious imbalance of intestinal microbiota and its metabolites. High-throughput sequencing showed that gastrointestinal bacterial community composition differed between male and female mice and was associated with susceptibility to radiation toxicity. Fecal microbiota transplantation (FMT) significantly increased the survival rate of irradiated animals, elevated peripheral white blood cell counts and improved gastrointestinal tract function and intestinal epithelial integrity in irradiated male and female mice. FMT also preserved the intestinal bacterial composition and retained mRNA and long non-coding RNA expression profiles of host small intestines in a sex-specific fashion. Intestinal flora intervention, including radioprotectors and hydrogen-rich water, significantly reduced the degree of acute radiation injury and animal mortality. The present proposal, based on a large number of preliminary studies, tests a hypothesis with the “intestinal flora and its metabolites play critical roles in controlling acute radiation syndrome. We will employ gene-engineering mouse and gut microbiota-free mouse to further study the critical roles of gut micobiota and its metabolites in development and progression of acute radiation injury in organs and tissues of irradiated mouse, and to explore of the feasibility of estimating the acute radiation injury for early triage by means of FMT and intestinal flora intervention. Large-scale screening of different biomarkers for assessment of acute radiation injury will be preformed based on sample analysis of of blood, urine and feces. It is expected that the coming findings from the present studies will provide theoretical and experimental evidence for intestinal flora and its metabolites as new evaluation system and FMT might serve as a therapeutic to mitigate radiation-induced injury. Therefore, this study has of important significance and value in both the basic research of acute radiation injury and the clinical application in the future.

快速、准确医学和剂量评估对核辐射突发事故下大规模受照人群的医学应对措施和救治至关重要。我们前期研究发现急性辐射损伤导致肠道菌群及其代谢产物严重失调，粪便移植和肠道菌群干预显著地降低了急性辐射损伤程度和动物死亡率。本项目拟在大量预实验研究的基础上，紧紧围绕“肠道菌群及其代谢产物改变是决定急性辐射损伤程度之关键”假设，采用基因工程鼠和无菌鼠辐射损伤模型，深入研究肠道菌群及其代谢产物参与组织器官急性辐射损伤发生发展关键作用及规律，深入探讨粪便移植和肠道菌群干预在急性辐射损伤救治关键技术及机制，并就此筛选出一系列血、尿、粪便急性辐射损伤评价的生物标志物。期望通过一系列临床前研究，为肠道菌群及其代谢产物作为新评价指标和救治手段在急性辐射损伤伤情评估和医学救治中应用提供必要的理论和实验研究依据和基础。因此，这项研究无论在急性辐射损伤的基础研究还是在将来救治临床应用研究都具有重要的临床意义和研究价值。

在核辐射突发意外事故的情况下，采取准确、快速的生物分析技术估算大规模受照人群的受照剂量，实施准确的医学应对措施、指导医学应急救援和临床救治，这是核辐射损伤防护、救治与康复的临床和基础研究重要和热点研究方向和课题。本项目在我们大量预实验和前期发表的研究结果基础上，提出了“肠道菌群及其代谢产物改变是决定急性辐射损伤程度的关键因素”一科学假设，并采用了Chk2+/+ (辐射敏感)和Chk2-/- (耐辐射) 基因工程鼠，正常肠道菌群鼠和无菌鼠等不同动物模型开展了一系列深入的科学研究，证实了通过改变肠道菌群和口腔菌群移植及其包括代谢产物确实可以影响gamma-射线和x-射线照射的动物机体不同程度辐射损伤严重程度，急性肠道辐射损伤存在着明显的性别差异。也发现包括富氢水，3,3'-二吲哚基甲烷，食品添加剂-乳化剂以及微塑料等都对急性全身辐射损伤和肠道辐射损伤产生不同程度的影响。我们证实血液、尿液、粪便等微生物和一些机体代谢产物改变检测可以作为急性辐射损伤生物标志物指标。我们的研究成果证实肠道菌群及其代谢产物与急性核辐射损伤的关系复杂而密切，可作为生物标记物、诊断与治疗靶点，是辐射损伤精准防治与康复不可缺少的因素，形成了大规模、大数据，多评价指标系统地为“急性辐射损伤→肠道菌群及其代谢产物改变→组织器官辐射损伤→生物标志物→防护、救治与康复”提供重要的实验基础和理论依据。这些研究结果毫无疑问将为急性辐射损伤发生发展规律、辐射损伤防护以及临床诊断、救治与康复疗效和预后提供了新的研究方向和思路。因此，本项研究无论在了解急性辐射损伤发生发展规律的基础实验和理论机制探索，还是可能发生的核辐射突发事故情况下，大规模受照射人群急性辐射损伤诊疗，提高临床急性核辐射损伤疗效、个体化治疗方案制定指导和康复预后评估临床应用研究都具有重要研究价值和应用前景。