基于RIP1的“选择性细胞因子抵抗”成因及其在糖尿病发病机制中的作用

It is widely believed that inflammation associated with obesity plays a central role in the development of type 2 diabetes mellitus (T2DM). So far, to dissect the different roles of diverse immune cells or different inflammation regulators in the development of T2DM has become the leading direction in this field of diabetes and obesity study. The applicant has found that a pro-inflammation kinase, IKKβ, could improve hepatic glucose homeostasis by suppressing ER stress in obese mice. In addition, the applicant further found that the sensitivity of p38 MAPK and IKKβ to TNFα is reduced and the inhibition of insulin resistance by p38 MAPK and IKKβ was lost in obesity. On the contrary, a parallel pathway, JNK was over-activated and its role in impairment of insulin signaling was elevated in obesity. The applicant termed this phenotype as “selective cytokines resistance”. The preliminary data revealed that the post-translation modification of RIP1 regulates p38 MAPK and IKKβ, which may play an important role in the development of “selective cytokines resistance”. This project will assess the novel post-translation modification of RIP1, explore the underlying mechanism of the development of “selective cytokines resistance” and its role in the development of insulin resistance. These efforts may provide a novel direction and foundation work for designing effective anti-diabetes treatments.

“炎症导致胰岛素抵抗”是本领域传统的观点，目前“探索不同免疫细胞或炎症因子在糖尿病中的不同作用”已成研究的热点，并不断产生许多新发现。申请人在传统研究的基础上，发现了促炎激酶IKKβ可以通过降低内质网应激，并提高机体胰岛素敏感性。在前期的研究过程中申请人发现，肥胖小鼠肝脏中受TNFα调控的p38 MAPK and IKKβ激活钝化，其提高胰岛素敏感性的作用缺失；而另一方面，同样受TNFα调控的JNK过度活化，其阻断胰岛素信号的作用被放大。申请人将这种选择性信号阻断的现象，命名为“选择性细胞因子抵抗”。申请人前期研究发现， RIP1翻译后修饰可能与“选择性细胞因子抵抗”有关。本项目拟通过研究肥胖机体中RIP1翻译后修饰的变化，揭示肥胖机体中“选择性细胞因子抵抗”的成因，以及造成胰岛素抵抗的分子机制，进而为糖尿病的治疗和药物研发提供新的理论依据。

项目负责人主要研究胰岛素抵抗和糖尿病病理机制。炎症发生及其促炎激酶与胰岛素抵抗的发生密切相关。RIP1是一种重要的促炎激酶，它通过激活下游的IKKβ激活炎症发生。本项目中，项目负责人及其团队聚焦于RIP1及其它胰岛素信号通路调控因子在糖尿病发病过程中的作用机制，相关研究成果包括（1）发现RIP1不激活下游炎症反应，直接结合胰岛素受体抑制胰岛素信号的机制；（2）发现TGFβ1转录抑制因子YY1，并开发了激活YY1抗糖尿病肾病的小分子（桉脂素，EDN）；（3）发展系统关联方法，开发了通过促脂肪产热抗肥胖的天然小分子贯叶连翘（HPF）和Indirubin；并开发有限水解酶法，发现并证明Dlat是HPF促进产热的直接靶点；（4）XBP1s是缓解内质网应激的关机调控元件，我们发现了XBP1s的泛素化调控机制，并证明抑制XBP1s泛素化降解有助于缓解内质网应激和胰岛素抵抗；（5）揭示了脂肪棕色化促进透明肾癌恶化的病理机制。