基于脱碘酶介导“脑-甲状腺”功能轴研究黄芩防治糖尿病脑病的作用机制

调节“脑-甲状腺”功能轴，开发具有神经内分泌系统保护功能的药物，是近年糖尿病脑病研究的热点之一。硒是人体必需的微量元素，脱碘酶作为重要的硒蛋白，是大脑中调节甲状腺激素信号强度的最主要因素，脱碘酶分泌失衡导致的内质网应激可能是“脑-甲状腺”轴功能紊乱关键环节，可能成为治疗2型糖尿病脑病的重要突破方向。本项目拟在中医药理论指导下，采用重组慢病毒构建的基因原位脱碘酶敲减/过表达动物模型、Sbp2条件敲除转基因动物模型以及相关分子生物学技术，重点研究Sbp2调节的脱碘酶通路与“脑-甲状腺”功能轴的作用关系，从而阐明中药黄芩、黄芩素调节神经内分泌系统改善糖尿病脑病的的关键调节因子及分子机制。在此基础上，从黄芩中敲除黄芩苷和黄芩素，探究黄芩、黄芩素、黄芩敲除黄芩苷和黄芩素三者之间药效异同及相互关系，阐明黄芩抗糖尿病脑病的药效物质基础，为临床合理用药提供理论依据，为中药现代化研究提供思路。

In recent years, it is one of the hot spots in the research of diabetic encephalopathy to regulate the "brain-thyroid" function axis and develop drugs with protection function on the neuroendocrine system. Selenium is an essential trace element in human body. Deiodinases as important selenium proteins, are the main factors regulating the intensity of thyroid hormone signal in the brain. The endoplasmic reticulum stress caused by the imbalance of deiodinases might be the key link of "brain-thyroid" axis dysfunction, which could become a major breakthrough in the treatment of type 2 diabetic encephalopathy. Under the guidance of traditional Chinese medicine theory and focusing on the study of the relationship between the deiodinase pathway regulated by Sbp2 and the "brain-thyroid" function axis, this project plans to use the gene in situ deiodinase knockdown/overexpression animal model constructed by recombinant lentivirus, Sbp2-conditional-knockout transgenic animal model and related molecular biology technologies, so as to clarify the key factors of Chinese medicine Radix Scutellariae in regulating the neuroendocrine system and its underlying molecular mechanism of improving diabetic encephalopathy. On this basis, we knock out baicalin and baicalein component from Radix Scutellariae, to explore the pharmacodynamic similarities and differences and interrelations between Radix Scutellariae, baicalein and the baicalin-and-baicalein-knockout, and clarify the pharmacodynamic material basis of Radix Scutellariae against diabetic encephalopathy, so as to provide theoretical basis for clinical rational drug use, and provide ideas for the modernization of traditional Chinese medicine.