组织蛋白酶G在1型糖尿病CD4+T细胞活化过程中的作用研究

Type 1 diabetes mellitus (T1D ) is a T-cell-mediated autoimmune disease characterized by destruction of insulin-producing β cells in the islets. It is thought that CD4+ T cells play predominant role throughout the pathogenesis of T1D. Studies with cathepsin knockout mice have addressed the question of whether cathepsins are directly involved in the development of autoimmunity. For example, experiments by using CatS, B, and L deficient mice indicated that these proteases are important in the onset of autoimmune diabetes. However, The serine protease, CatG, dominates the processing of antigens and autoantigens, whose role in T1D and the effect of CatG inhibitor on the T1D are poorly understood, our previous study found that CatG plays a critical role in proinsulin processing and subsequent activation of diabetogenic T cells and specific CatG inhibitor might used to mitigate the activation of diabetogenic T cells in vivo. Therefore, our hypothesis is that CatG plays a key role in the activation of CD4+ T cells in T1D. To this end, the relationship between the level of CatG and the activation of CD4+ T cells in T1D will be explored. Non-obese diabetic mouse(NOD) will be taken as animal model, the activation of CD4+ T cells and occurrence of diabetes will be obsevered after CatGsiRNA treatment in pre-diabetic NOD mice. Furthermore the effect of CatG inhibitor on the activation of CD4+ T cells, islet function, inflammation, and β cell apoptosis will be determined in NOD mice. Our results may identify CatG as an enzyme whose activity is essential for the activation of CD4+ T cells in the development of T1D in NOD mice and the specific inhibition of CatG as a powerful therapeutic strategy for autoimmune diabetes will be demonstrated.

1型糖尿病（T1D）是一种由T细胞介导的自身免疫性疾病，T细胞活化是T1D的启动步骤。我们前期研究发现组织蛋白酶G(CatG）参与胰岛素原的抗原递呈；同时体外研究发现CatG抑制剂可以减轻T1D患者胰岛素原诱导的CD4+ T细胞活化。因此，我们推测CatG在1型糖尿病CD4+ T细胞活化过程中发挥着重要的作用。由此，本课题拟在探讨T1D患者CatG水平与CD4+ T细胞活化相关性的基础上，利用非肥胖糖尿病（NOD）小鼠模型，在体运用CatGsiRNA来观察其对非糖尿病时期NOD小鼠CD4+ T细胞活化状态及糖尿病发生的影响，并进一步检测CatG抑制剂治疗糖尿病小鼠对CD4+ T细胞活化、胰岛功能、胰岛炎症及β细胞凋亡的影响。旨在从在体水平证实CatG是T1D体内致糖尿病T细胞活化的主要效应蛋白酶，为将来运用免疫抑制治疗T1D提供新的理论和实验依据。

1型糖尿病（T1DM）是一种由T淋巴细胞介导的胰岛β细胞进行性损伤的自身免疫性疾病。我们前期研究发现只有组织蛋白酶G (CatG)，而非其他类蛋白酶参与胰岛素原的抗原递呈，其抑制剂可以减轻T1DM 患者胰岛素原诱导的CD4+ T 细胞活化。因此本课题拟在非肥胖糖尿病（NOD）小鼠中验证调节CatG的表达可以影响CD4+ T细胞的活化水平。本研究通过检测NOD小鼠中CatG的表达与CD4+ T细胞活化状态。观察CatG抑制剂治疗糖尿病小鼠对CD4+ T细胞活化、胰岛功能、胰岛炎症及胰岛β细胞凋亡的影响。并进一步观察早期运用CatG siRNA对NOD小鼠CD4+ T细胞活化状态及糖尿病进程的影响。结果发现，随着糖尿病的发生，NOD小鼠CatG的表达水平逐渐升高，CD4+ T细胞逐渐活化，表现为TH1细胞升高，TH2和Treg细胞下降。在体运用特异性CatG抑制剂能够降低小鼠血糖，改善胰岛功能，并且能够减轻CD4+ T细胞的活化水平。早期运用CatG siRNA可以改善胰岛功能，减轻胰岛炎症和胰岛β细胞的凋亡，减轻CD4+ T细胞的活化，进而延缓糖尿病的进程。因此，我们得出结论：CatG是T1DM发病中CD4+ T细胞活化过程中的主要效应蛋白酶。特异性阻断CatG可以通过抑制CD4 + T细胞的活化保护胰岛β细胞功能，延缓或阻断T1DM的发生发展，为将来运用CatG抑制剂治疗T1DM提供了新的理论和实验依据。

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