Effect of the autoimmune suppressor Gadd45a on radiation biodosimetry

Radiation biodosimetry based on transcriptomic analysis of peripheral blood is a valuable tool to detect radiation exposure after a radiological/nuclear event and obtain useful biological information that could predict tissue and organismal injury. However, confounding factors, including inflammation, can potentially obscure the predictive power of the method. The Gadd45 (growth arrest and DNA damage-inducible genes) family is composed of three members, Gadd45a, Gadd45b, and Gadd45g, that play important roles in cell growth control, differentiation, DNA repair, and apoptosis. Gadd45b and Gadd45g are important for inflammatory responses as well as mediating signals of the innate immune system, whereas Gadd45a is a negative regulator of activation-induced T cell proliferation. T cells from Gadd45a null mice are hyper-responsive to activating stimuli due to spontaneously increased p38MAPK activity. Importantly, Gadd45a-deficient mice develop an autoimmune disease, similar to human systemic lupus erythematosus, characterized by severe hematological disorders, kidney disease, and premature death. The goal of this study was to elucidate how pre-existing inflammatory condition in mice can affect radiation biodosimetry. We exposed wild-type and Gadd45a knockout C57BL/6J mice to 7 Gy x-rays and 24 h later we isolated whole blood and performed genome microarray and gene ontology analysis. Radiation induced gene expression in blood from Gadd45aWT and Gadd45aKO mice was measured 24 h after 7 Gy of x-rays. Five or 9 (gadd45aKO_IR) independent experiments were performed at each Gadd45 genotype and treatment.

基于外周血转录组分析的辐射生物剂量测定（radiation biodosimetry）是检测放射/核事件后辐射暴露，并获取可预测组织与机体损伤的有效生物学信息的重要工具。然而，包括炎症在内的混杂因素可能会削弱该方法的预测效能。Gadd45（生长阻滞与DNA损伤诱导基因，growth arrest and DNA damage-inducible genes）家族包含三个成员：Gadd45a、Gadd45b与Gadd45g，它们在细胞生长调控、分化、DNA修复及细胞凋亡中发挥关键作用。Gadd45b与Gadd45g在炎症应答以及介导先天免疫系统信号通路中具有重要功能，而Gadd45a则是激活诱导T细胞增殖的负调控因子。来自Gadd45a敲除（Gadd45a null）小鼠的T细胞对激活刺激呈现高反应性，这源于其体内p38丝裂原活化蛋白激酶（p38MAPK）活性自发升高。尤为重要的是，Gadd45a缺陷小鼠会罹患自身免疫性疾病，其病症与人类系统性红斑狼疮相似，表现为严重血液系统紊乱、肾脏病变及过早死亡。本研究旨在阐明小鼠体内预先存在的炎症状态会如何影响辐射生物剂量测定。我们将野生型与Gadd45a敲除（Gadd45a knockout）C57BL/6J小鼠暴露于7戈瑞X射线中，并在24小时后采集全血，开展全基因组微阵列分析与基因本体论（gene ontology）分析。我们检测了7戈瑞X射线照射24小时后，Gadd45a野生型与Gadd45a敲除型小鼠血液中辐射诱导的基因表达水平。每种Gadd45基因型与处理组分别开展了5次或9次（gadd45aKO_IR）独立实验。