基于对胰腺β细胞保护作用的AIF-1抗体预防1型糖尿病的机制研究

1型糖尿病是一种免疫细胞介导、以胰腺β细胞损伤为特征的自身性免疫疾病，目前临床上主要依靠终身补充外源胰岛素维持患者生命。申请人前期研究显示异体移植炎症因子1(AIF-1)体外损伤了胰腺β细胞，体内加速了NOD模型鼠1型糖尿病的发生，加剧了其胰腺β细胞量的减少，而AIF-1抗体可有效防止模型鼠胰岛炎并阻止其胰腺β细胞的损伤，说明AIF-1是1型糖尿病的直接致病因子，而其抗体可用于预防1型糖尿病。本项目拟探索AIF-1抗体预防1型糖尿病的方案，并通过研究AIF-1对胰腺β细胞凋亡的影响，垂钓其在胰腺β细胞上（中）的相互作用因子（受体），构建其下游信号转导通路，进而揭示AIF-1影响胰腺β细胞的途径，及AIF-1抗体对这些影响的拮抗，阐明AIF-1抗体保护胰腺β细胞的分子机制，为1型糖尿病抗体药物的开发奠定基础。

Type 1 diabetes is a multifactorial autoimmune disease characterised by immunocyte cell mediated destruction of beta cells in the pancreas. Although daily insulin injection ameliorates the disease, it does not provide physiological level of the hormone. A safe, potent, and practical approach that can treat the disease via protecting beta cell from impairment is needed. We previously reported that inflammatory cytokine allograft inflammatory factor 1(AIF-1) accelerated type 1 diabetes with reduced beta cell mass, and the antibody against it prevented insulitis and beta cell disruption in non-obese diabetic (NOD) mice, suggesting that AIF-1 plays a critical role in beta cell loss in type 1 diabetes and its antibody could prevent this disease by protecting beta cell from disruption. In the present study, we intend to explore an approach to prevent type 1 diabetes by the antibody, further examine the protecting effect of this antibody on beta cell from apoptosis, purify the interacting factor(s) of AIF-1 on (in) beta cell, define the downstream signal transduction pathways activated by AIF-1, clarify the essential molecular mechanism of the antibody against AIF-1 protecting beta cells, develop the antibody as a new drug in the treatment/prevention of type 1 diabetes. .