miRNA-34a/FoxM1调节胰岛微血管内皮细胞衰老在年龄相关胰岛功能衰退中的作用机制

Age-related islet dysfunction plays an important role in the pathological process of type 2 diabetes. A growing body of evidence supports the concept that cellular senescence of islet microvascular endothelial cells (IMECs), not the aging of β-cell itself, contributes significantly to age-related islet dysfunction. miRNAs are a class of non-coding RNAs that regulate gene expression and are differentially expressed in cellular senescence. Our preliminary study shows that the level of miR-34a expression in IMECs of aging model mice is higher than that in young mice and that silencing miR-34a can attenuate cellular senescence of IMECs. Bioinformatics analysis suggests that miR-34a can target a transcription factor FoxM1. Our preliminary study also confirms that FoxM1 can regulate the proliferation of IMECs. However, there is no relevant report over mechanism of cellular senescence of IMECs by miR-34a/FoxM1 pathway. We hypothesize that miR-34a/FoxM1 contributes to age-related islet dysfunction in vivo through regulating cellular senescence of IMECs. We will test the hypothesis using endothelial specific miR-34a gene knockdown and overexpression mouse models. Our study will have implications in understanding and treatment of age-related islet dysfunction.

年龄相关胰岛功能衰退是2型糖尿病发病核心环节。研究证实胰岛β细胞本身未随年龄增长出现功能障碍，胰岛微血管内皮细胞衰老才是胰岛功能衰退的始动因素。miRNA是一类调控基因表达的非编码RNA并在细胞衰老中差异性表达。我们预实验发现衰老小鼠胰岛微血管内皮细胞miR-34a表达上调，而沉默miR-34a缓解内皮细胞衰老。生物信息学分析示FoxM1的mRNA中存在miR-34a的结合位点。我们前期工作表明FoxM1调控胰岛微血管内皮细胞增殖，但miR-34a/FoxM1调控胰岛微血管内皮细胞衰老的机制未见报道。据此假设：miR-34a通过FoxM1调控胰岛微血管内皮细胞衰老，进而影响胰岛β细胞功能。本研究拟采用内皮特异性miR-34a基因敲除及过表达小鼠为模型，从分子、细胞、动物水平探讨miR-34a/FoxM1是否调控胰岛微血管内皮细胞衰老，以期为年龄相关胰岛功能衰退的防治提供新思路和新方法。

2型糖尿病是与年龄密切相关的代谢性疾病，衰老相关性胰岛β细胞功能衰退是其发病的核心环节之一。胰岛微循环内皮细胞衰老是胰岛β细胞功能衰退的始动环节，并贯穿糖尿病胰岛功能障碍发生、发展的始终。因此，延缓胰岛微循环内皮细胞衰老，是防治年龄相关胰岛β细胞功能衰退的关键环节。研究组前期预实验发现，老龄化小鼠胰岛微循环内皮细胞及体外胰岛微循环内皮细胞衰老模型中miR-34a表达明显升高，同时,生物信息学分析显示miR-34a和FoxM1基因3’UTR区存在结合位点。由此研究组提出假设，miR-34a通过调节FoxM1表达调控胰岛微循环内皮细胞衰老，在年龄相关的糖尿病发病过程中发挥重要作用。基于上述研究结果及实验支持，研究组通过动物、细胞及分子实验验证了如下结论：1、miR-34a参与胰岛微循环内皮细胞的衰老；2、FoxM1调控胰岛微循环内皮细胞的衰老；3 miR-34a通过Bcl2，Sirt1，FoxM1等基因调控胰岛微循环内皮细胞衰老。本研究创新性的选择胰岛微循环系统作为年龄相关胰岛功能衰退的研究切入点，从分子、细胞、动物多层次观察miR-34a对胰岛微循环内皮细胞衰老的影响，以期为年龄相关2型糖尿病的早期预防与干预策略提供新的思路和科学依据。本研究预期结果为2型糖尿病的防治提供新的靶点，或可引领传统糖尿病防治理念的革新，开辟新的糖尿病治疗领域，为解决糖尿病这一社会公共健康问题做出贡献。