糖化终末产物诱导胰岛β细胞炎性损伤的分子机制研究

胰岛β细胞功能进行性减退是2型糖尿病突出的病理生理基础，其机制尚未完全阐明。申请者的前期研究显示，葡萄糖的衍生物糖化终末产物(AGEs)可导致β细胞活性氧(ROS)生成增加，造成细胞损伤，同时观察到NLRP3炎症小体表达上调及白细胞介素-1β(IL-1β)分泌增加，用AGEs受体特异性抗体阻断相关信号转导可逆转上述变化。本项目拟在此基础上进一步探讨AGEs及相关阻断措施（RAGE、ROS、NLRP3、ASC、Caspase-1及IL-1β阻断）对MIN6细胞及培养的小鼠胰岛NLRP3-ASC-Caspase 1-IL-1β系统及胰岛素分泌功能的影响；并观察给予AGEs对正常小鼠、Nlrp3-/-、Pycard-/-和Casp-1-/-小鼠β细胞的影响。本项目旨在阐明NLRP3炎症小体在AGEs诱导的β细胞损伤中的关键作用，为β细胞保护开辟新思路，并在分子水平上揭示免疫-代谢相互作用及机制。

Progressive deterioration of β cell function is the prominent pathophysiological feature of type 2 diabetes. However,the related mechanisms have not been completely elucidated. Recently, we have revealed the fact that increased reactive oxygen species (ROS) production in islet β cells could be induced by glucose-derived advanced glycation end products (AGEs), which results in cell damage. We also found that AGEs upregulated NLRP3 expression level and increased secretion of interleukin-1β (IL-1β). Furthermore, these abnormalities were essentially reversed by inhibition of receptor for AGEs (RAGE) by pretreatment with neutralizing anti-RAGE antibody. All of these evidences suggest that the NLRP3 inflammsome may be involved in AGEs-induced pancreatic β cell damage. As a result, this project is designed for the following purposes: first, to investigate the effects of AGEs on ROS-NLRP3-ASC-Caspase 1-IL-1β pathway and insulin secretion in β cells; second, to evaluate the effects of interventions, such as blocking RAGE, ROS, NLRP3, ASC, Caspase 1 or IL-1β, on AGEs-induced β cell damage; third, to investigate the effects of intraperitoneal administration of AGEs on islet β cells in normal, Nlrp3-/-, Pycard-/- and Casp 1-/- mice. Taken together,the implementation of this study will not only help to clarify the role of the NLRP3 inflammasome in the phenomenon of AGEs-induced pancreatic β cell damage and explore a new insight for the protection of pancreatic β cells, but also reveal the molecular mechanisms of immune-metabolic interactions.