Extl3缓解1型糖尿病胰岛β细胞破坏的作用与机制研究

1型糖尿病是一种慢性自身免疫性疾病，存在异常激活的免疫细胞破坏胰岛基底膜而侵入胰岛并攻击β细胞的现象。作为参与基底膜中硫酸乙酰肝素合成的关键基因，外生骨疣样蛋白3（Extl3）不仅对β细胞成熟起关键作用，而且在β细胞受到IL-1β等炎症因子刺激后表达水平迅速下调。通过实验我们发现，小鼠胰腺原位注射shExtl3腺相关病毒可下调β细胞内Extl3的蛋白水平，并加重链脲佐菌素（STZ）诱导的胰岛炎及胰岛功能损伤，提示Extl3在1型糖尿病发病过程中可能起重要作用，但机制仍不清楚。申请人拟于1型糖尿病模型小鼠β细胞中特异性敲降或过表达Extl3，验证Extl3通过促进硫酸乙酰肝素合成而缓解β细胞的免疫损伤；利用谱系示踪实验，观测Extl3在1型糖尿病β细胞去分化中的作用；细胞水平上借助炎症因子刺激，进一步探究Extl3表达水平下调介导β细胞损伤的分子机制。希望本研究能为1型糖尿病防治带来新思路。

Type 1 diabetes is a chronic autoimmune disease, in which abnormally activated immune cells destroy the basement membrane, infiltrate the islets, and attack the β cells. As a key gene for heparan sulfate synthesis in the islet basement membrane, exostoses-like 3 protein (Extl3) plays a key role in β-cell maturation and inflammatory factors such as IL-1β rapidly decreases the expression of Extl3 in β-cells. Additionally, we found that in situ injection of shExtl3 adeno-associated virus in mouse pancreas can down-regulate the protein level of Extl3 in pancreatic β cells, and aggravate insulitis and islet function damage induced by streptozotocin (STZ). The facts suggest that Extl3 might play an important role in the pathogenesis of type 1 diabetes, but the mechanism is still to be deciphered. This study intends to use specific knockdown or overexpression of Extl3 in β cells of type 1 diabetes model mice to verify that Extl3 mitigates immune damage to β cells by promoting heparan sulfate synthesis; The lineage tracing study is used to observe that the function of Extl3 in β-cell dedifferentiation; The molecular mechanism of Extl3 downregulation mediating β-cell injury is further explored by treatment of inflammatory factors. The study would bring new ideas for the prevention and treatment of type 1 diabetes.