Diamantina Institute, Translational Research Institute, University of Queensland , Woolloongabba, Queensland, Australia.
St Vincent's Institute , Fitzroy, Victoria, Australia.
Clin Transl Immunology. 2015 Aug 28;4(8):e41. doi: 10.1038/cti.2015.17. eCollection 2015 Aug.
In the NOD mouse model of type 1 diabetes (T1D), genetically identical mice in the same environment develop diabetes at different rates. Similar heterogeneity in the rate of progression to T1D exists in humans, but the underlying mechanisms are unclear. Here, we aimed to discover peripheral blood (PB) genes in NOD mice predicting insulitis severity and rate of progression to diabetes. We then wished to use these genes to mine existing databases to identify drugs effective in diabetes. In a longitudinal study, we analyzed gene expression in PB samples from NOD.CD45.2 mice at 10 weeks of age, then scored pancreatic insulitis at 14 weeks or determined age of diabetes onset. In a multilinear regression model, Tnf and Tgfb mRNA expression in PB predicted insulitis score (R (2)=0.56, P=0.01). Expression of these genes did not predict age of diabetes onset. However, by expression-profiling PB genes in 10-week-old NOD.CD45.2 mice, we found a signature of upregulated genes that predicted delayed or no diabetes. Major associated pathways included chromatin organization, cellular protein location and regulation of nitrogen compounds and RNA. In a clinical cohort, three of these genes were differentially expressed between first-degree relatives, T1D patients and controls. Bioinformatic analysis of differentially expressed genes in NOD.CD45.2 PB identified drugs that are predicted to delay or prevent diabetes. Of these drugs, 11 overlapped with drugs predicted to induce a human 'non-progressor' expression profile. These data demonstrate that disease heterogeneity in diabetes-prone mice can be exploited to mine novel clinical T1D biomarkers and drug targets.
在 1 型糖尿病（T1D）的 NOD 小鼠模型中，相同环境下遗传相同的小鼠发生糖尿病的速度不同。人类 T1D 的进展速度也存在类似的异质性，但潜在机制尚不清楚。在这里，我们旨在发现预测胰岛炎严重程度和向 T1D 进展速度的 NOD 小鼠外周血（PB）基因。然后，我们希望使用这些基因挖掘现有的数据库，以确定治疗糖尿病的有效药物。在一项纵向研究中，我们分析了 10 周龄 NOD.CD45.2 小鼠 PB 样本中的基因表达，然后在 14 周时对胰腺胰岛炎进行评分或确定糖尿病发病年龄。在多线性回归模型中，PB 中 Tnf 和 Tgfb mRNA 的表达可预测胰岛炎评分（R (2)=0.56，P=0.01）。这些基因的表达并不能预测糖尿病发病年龄。然而，通过对 10 周龄 NOD.CD45.2 小鼠 PB 基因进行表达谱分析，我们发现了一个上调基因的特征，该特征可预测糖尿病的延迟或不发生。主要相关途径包括染色质组织、细胞蛋白定位以及氮化合物和 RNA 的调节。在一个临床队列中，这些基因中的三个在一级亲属、T1D 患者和对照组之间存在差异表达。NOD.CD45.2 PB 中差异表达基因的生物信息学分析确定了可预测延迟或预防糖尿病的药物。在这些药物中，有 11 种药物与预测可诱导人类“非进展者”表达谱的药物重叠。这些数据表明，糖尿病易感小鼠的疾病异质性可用于挖掘新的临床 T1D 生物标志物和药物靶点。
