Chemerin/ChemR23轴对糖尿病认知功能障碍的作用机制及靶向治疗研究

Chemerin/ChemR23轴调控SIRT1/NF-κB通路引起异常炎症反应，在糖尿病外周器官病变中发挥重要作用。但其对糖尿病认知功能障碍的作用仍不清楚。我们的前期工作发现chemerin和ChemR23在阿尔茨海默病和高脂饮食等模型中有异常改变，故该轴可能对糖尿病认知障碍的发生发展起到重要作用。本项目将利用临床样本研究chemerin/ChemR23轴在糖尿病认知障碍病人中的改变特点；运用细胞模型探讨其对小胶质细胞炎症反应、清除Aβ能力及对神经元tau蛋白的影响；使用动物模型明确其对脑内炎症、Aβ和tau代谢以及行为学的影响机制；同时用特化促消退介质RvE1进行靶向干预研究，以证明chemerin/ChemR23轴通过SIRT1/NF-κB通路影响糖尿病认知障碍，而RvE1则可以靶向干预该轴。研究成果将对阐明糖尿病认知功能障碍的发病机制具有重要意义，也为开发靶向治疗药物奠定基础。

Chemerin/ChemR23 axis induces inflammation through SIRT1/ NF-κB pathways, and plays an important role in diabetes mellitus related peripheral diseases. However, it is not known if chemerin/ChemR23 axis plays a role in diabetic cognitive impairment. We have previously found that chemerin/ChemR23 axis is altered in Alzheimer’s disease and high fat/cholesterol diet induced cognitive impairment models, suggesting a role of chemerin/ChemR23 pathway in diabetic cognitive impairment. In this study, we will explore the changes of chemerin/ChemR23 axis in patients with diabetic cognitive impairment by using clinical samples, and elucidate how chemerin/ChemR23 axis influences inflammatory response and phagocytosis of Aβ in microglia, and how this axis affects tau metabolism in neuron. We will also utilize animal models of diabetic cognitive impairment to study the mechanism of how chemerin/ChemR23 axis modulates neuroinflammation, Aβ and tau in the brain, as well as its behavioral effects in the animals. Meanwhile, specialized pro-resolving mediator RvE1 will be tested as a novel therapeutic method targeting chemerin/ChemR23 axis. Our study will demonstrate chemerin/ChemR23 axis plays a key role in diabetic cognitive impairment through SIRT1/ NF-κB pathways, and RvE1 can target this axis to treat diabetic cognitive impairment. Our study will improve the understanding of the mechanism of diabetic cognitive impairment, and provide fundamental evidence for developing novel targeted drugs.