Tetraspanin 7/PICK1通路介导糖尿病认知功能障碍的机制研究

糖尿病已被证实可显著增加认知功能障碍发生风险，随着中国和全球人口老年化，糖尿病患病人群快速增长，糖尿病认知功能障碍的发生率将进一步增加。然而，目前糖尿病所致认知功能障碍的具体机制尚未阐明。我们前期研究发现tetraspanin 7（TSPAN7）在正常小鼠海马区神经元高度表达，并且首次发现TSPAN7在认知功能障碍的糖尿病小鼠海马神经元和高糖培养原代海马神经元中表达下降。TSPAN7可与PICK1的PDZ结构域结合，进而调节突触结构和神经元凋亡。据此提出科学假说：TSPAN7可通过调控PICK1作用于海马神经元，介导糖尿病认知功能障碍的发生。本项目将通过研究海马神经元凋亡和突触结构改变，阐明TSPAN7/PICK1通路导致糖尿病认知功能障碍发生的分子机制。本项目以TSPAN7/PICK1通路为核心，力求揭示糖尿病所致认知功能障碍的新机制，并为后续的药物筛选提供潜在的治疗靶点。

There is strong evidence that diabetes predisposes to cognitive impairment. As the Chinese and global populations aging, the number of people with diabetes grows fast, and the incidence of diabetes-related cognitive impairment will increase further. However, the exact pathophysiology of cognitive dysfunction in diabetes has not yet been elucidated. Our preliminary study found that tetraspanin 7 (TSPAN7) was highly expressed in the hippocampal neurons of normal mice and found that the expression of TSPAN7 decreased in hippocampal neurons of diabetic mice with cognitive impairment and high-glucose cultured primary hippocampal neurons for the first time. TSPAN7 can bind to the PDZ domain of PICK1 and then regulate synaptic structure and neuronal apoptosis. According to those facts, we propose TSPAN7 can regulate the occurrence of diabetes-related cognitive impairment by regulating PICK1 on hippocampal neurons. This study will elucidate the molecular mechanism of the occurrence diabetes-associated cognitive impairment by the TSPAN7/PICK1 pathway by studying hippocampal neuronal apoptosis and synaptic structural changes. Given the TSPAN7/PICK1 pathway as the core perspective, this project will strive to reveal the new mechanism of the pathogenesis of diabetes-related cognitive impairment and provide potential therapeutic targets for subsequent drug discovery screening.