二肽基肽酶对代谢性炎症的调控作用及其机制研究

Recent evidence indicates that persistent low-grade inflammation is an important pathological character in diabetes. Therefore, metabolic inflammation has received increasing attention in the area of diabetes research. Dipeptidyl peptidase 4 (DPP4) is a widely expressed enzyme that regulates blood glucose by cleaveing incretins such as GLP-1 and GIP. The investigator's preliminary work suggests that DPP4 plays an essential role in obesity-induced insulin resistance and diabetes by regulating metabolic inflammation. Our preliminary studies indicate that DPP4 expression on macrophage and T cells significantly increased in patients with diabetes or dyslipidemia. Its expression was positively correlated with plasma lipid levels. Subsequent experiments suggest DPP4 regulates T cell activation via interacting with ADA. DPP4 deficient T cells showed a reduced migratory activity. This study aims to investigate the regulatory role of DPP4 in metabolic inflammation and diabetes using human samples from diabetes patients and a number of animal models. This application will also test therapeutic potential of DPP4 suppression in improving insulin resistance in diabetes.

研究表明持续低水平的炎症是导致糖尿病的重要因素，抑制代谢性炎症反应已经成为目前糖尿病病治疗的主要研究方向之一。二肽基肽酶4（dipeptidyl peptidase 4，DPP4）是体内广泛表达的一种蛋白酶，可通过降解GLP-1和GIP等促胰素而调节血糖。申报人前期工作提示DPP4还能通过其非酶学作用调节代谢性炎症而参与肥胖诱导的胰岛素抵抗和糖尿病发病。糖尿病和脂质代谢异常患者体内巨噬细胞和T细胞表达DPP4水平显著高于健康对照，且与血脂水平呈正相关。后续实验证实DPP4可通过与ADA相互作用而调控T细胞活化，DPP4缺陷小鼠T细胞迁移能力降低。本项目拟利用糖尿病病人样品和多种动物模型探讨DPP4对糖尿病中代谢性炎症的调节作用。本项目还将探索干预DPP4介导的代谢性炎症的治疗手段，从而达到缓解胰岛素抵抗，治疗糖尿病的目的。

本项目按计划顺利开展。项目执行以来，实验已取得良好进展，按照预定研究计划，完成了原定计划中的各项研究目标，共发表标注本项目资助的SCI论文7篇(影响因子总计86.8，单篇影响因子最高34.915)，参与1次国际学术会议和2次国内会议主持，在项目执行期间还获得了多项奖励和荣誉（省级人才奖项1项、市级人才奖项1项、国际学术奖项1项）。.本项目已顺利完成既定研究目标：1）阐明DPP4表达调控机制：肥胖诱导的氧化脂质（如oxLDL）增加可通过CD36和TLR4/TRIF通路上调DPP4表达；2）DPP4在糖尿病中对炎症的调节作用：发现DPP4敲除小鼠糖耐量实验、葡萄糖钳夹实验反应性改善，通过骨髓移植实验发现，非髓系细胞DPP4缺陷是引起DPP4敲除小鼠糖耐量改善的主要因素，髓系细胞DPP4缺陷则主要引起代谢性炎症改善；3） 探索新型策略阻断DPP4-ADA相互作用和糖尿病炎症：发现中东呼吸综合征冠状病毒（MERS-CoV）棘蛋白受体结合域（S-RBD）多肽可通过结合DPP4而竞争性抑制ADA与T细胞表面DPP4的结合，从而抑制DPP4介导的T细胞活化。