天麻素抑制转甲状腺素蛋白解聚改善糖尿病性小脑功能障碍的机制研究

临床发现糖尿病会造成认知受损，这与患者小脑损伤有关，但其分子机制不明确。申请人前期通过转录组学研究发现，糖尿病鼠小脑组织中转甲状腺素蛋白（TTR）水平升高，且解聚形成单体。小脑内TTR解聚是否与糖尿病性小脑功能障碍（CDD）有关尚不清楚。我们以往的研究表明，天麻素可以减轻糖尿病引起的浦肯野细胞损伤，进而改善认知功能。进一步实验发现，天麻素可以降低TTR单体水平。因此，我们假设天麻素通过稳定小脑TTR构象减轻糖尿病引起的小脑神经元损伤和小脑功能障碍。本课题拟构建转基因小鼠并诱导糖尿病模型，应用天麻素，通过分子生物学、fMRI和动物行为学检测，探究：1）TTR单体导致CDD的分子机制；2）天麻素是否通过调控小胶质细胞活化和稳定TTR蛋白构象而减轻CDD。本课题的结果将为拓展云南优势特色天然药物新用途提供理论依据。

Clinically, diabetes could cause cognitive impairment, which is correlated with cerebellar injury in diabetic patients. However, its underlying mechanism remains unclear. In our preliminary studies, the result of transcriptome analysis showed that the expression of transthyretin (TTR) was increased in the cerebellum of diabetic mice. Furthermore, TTR tetramer was dissociated into monomer. The relationship between TTR dissociation in the cerebellum and cerebellar dysfunction in diabetes (CDD) remains elusive. Our previous study showed that gastrodin could ameliorate Purkinje cell injury in diabetes and thus improve cognitive function. Further research found that gastrodin reduced the expression of TTR monomer. Therefore, we hypothesize that gastrodin may ameliorate cerebellar injury and thus CDD through stabilizing TTR. In light of this, with transgenic mice and type 1 diabetic model, we would use gastrodin and apply molecular biotechnology, fMRI and animal behavior assessments to investigate 1) the mechanism of TTR monomer leading to cognitive impairment and cerebellar injury, 2) the involvement of gastrodin on amelioration of CDD through modulating microglial activation and stabilizing TTR. More importantly, results derived from this study would provide a reliable theoretical basis for the new application of natural products from Yunnan Province.