Molecular Profiling of NOD mice reveals a novel regulator of insulitis onset

Non-obese Diabetes (NOD) mice are an established spontaneous model for Type 1 Diabetes (T1D), emulating diabetes development through insulitis. Using next generation sequencing, coupled with pathways analysis, the molecular fingerprint of early insulitis was mapped in a cohort of mice ranging from four to 12 weeks of age. The resulted dynamic timeline revealed an initial decrease in proliferative capacity followed by the emergence of an inflammatory signature between 6- and 8-weeks, that increases to a regulatory plateau between 10- and 12-weeks. The inflammatory signature is identified by activation of central immunogenic factors such as Infg, Il1b, Tnfa, and activation of canonical inflammatory signalling. Prodding of the regulatory landscape identified the transcription factor Atf3 as a potential novel regulator of inflammatory signalling in the NOD Islet. Furthermore, the Hedgehog (Hh) signaling pathway correlated with Atf3 regulation, hinting at role for the two in regulating the inflamed islet, however, further studies are needed to establish the nature of this connection. Islets were collected from NOD mice at 2 week intervals between 4-12 weeks of age for Bulk RNAseq. Aim: Investigate the gradual development of insulitis in the NOD mice.非肥胖糖尿病（Non-obese Diabetes, NOD）小鼠是1型糖尿病（Type 1 Diabetes, T1D）的经典自发模型，可通过胰岛炎进程模拟糖尿病的发生发展。本研究采用下一代测序（next generation sequencing）结合通路分析（pathways analysis），对4至12周龄小鼠队列的早期胰岛炎分子特征谱进行了系统绘制。所得动态时间轴结果显示，小鼠的增殖能力先出现下降，随后在6至8周龄时出现炎症特征谱，并在10至12周龄时上升至调控平台期。该炎症特征谱以Infg、Il1b、Tnfa等核心免疫原性因子的激活，以及经典炎症信号通路的活化作为标志性特征。对调控图谱的深入剖析发现，转录因子Atf3可作为NOD小鼠胰岛中炎症信号通路的潜在新型调控因子。此外，刺猬（Hedgehog, Hh）信号通路与Atf3的调控存在显著关联，提示二者可能共同参与调控炎症状态下的胰岛功能，但二者之间的具体关联机制仍需进一步研究阐明。本研究从4至12周龄的NOD小鼠中每隔2周采集胰岛样本，用于批量RNA测序（Bulk RNAseq）。本研究的目的为：探究NOD小鼠胰岛炎的渐进性发展过程。