糖尿病认知障碍发病轨迹及基于方证相关的中药干预研究

60% to 70% of Diabetes mellitus (DM) patients comply with mild to moderate cognitive impairment, or even develop dementia. "Intervention process" is the best prevention strategy. Early identification of cognitive impairment, to grasp the disease progression and syndrome evolution objectively (grasp the "process"), are the keys to the "process intervention" and drug discovery. So we propose the following hypothesis: there are specific biomarkers in cerebrospinal fluid of diabetes-associated cognitive impairment, they maybe show qualitative and/or quantitative process in diabetes-associated cognitive impairment process, which may integrate the appearance of symptoms and laboratory parameters to characterize syndromes evolution of diabetes-associated cognitive disorders and to guide the Traditional Chinese Medicine (TCM) dialectical interventions. This project intends to combined non-target and target metabolomics methods and techniques, be based on the main line of diabetes-associated cognitive impairment emergence and development, to screen the biomarkers of diabetes-associated cognitive impairment. We will track the changes of biomarkers, the appearance of symptoms, and related laboratory indicators over time to characterize trajectory diabetes-associated cognitive impairment onset and realize natural evolution of their internal relationship with TCM "syndrome" in diabetes-associated cognitive impairment. In order to provide foundation for early identification, guide and evaluate intervention of diabetes-associated cognitive impairment, Berberine-ginger, ginseng-Shichangpu drug were used as a model drug to evaluate the status and role of "formula and syndrome related" in DM interventions for cognitive impairment.

糖尿病（DM）患者中60%~70% 伴轻中度认知功能障碍，甚或发展为痴呆。“过程干预”是其最佳防治策略。早期识别认知障碍、客观把握疾病进程及证候演变规律（对“过程”的把握）是实现“过程干预”和药物发现的关键。为此提出如下假说：DM认知障碍大鼠脑脊液中存在特异性生物标记物，它们在DM认知障碍进展中呈现质和/或量变过程，且可与外观症候、实验室指标共同表征DM认知障碍中医证候演变规律，并以此指导DM认知障碍的中药辨证干预。本项目拟联合应用非靶标及靶标代谢组学等方法与技术，以DM认知障碍发生与进展为主线，筛选DM认知障碍生物标记物；并以生物标记物、外观症候、相关实验室指标经时变化为轨迹，表征DM认知障碍发病轨迹及与DM认知障碍中医“证”的自然演变过程的内在联系。为DM认知障碍早期识别、指导和评价干预效果奠定基础。以黄连-干姜、西洋参-菖蒲药对为模型药物，评价“方证相关”在DM认知障碍干预中的地位与作用。

课题组按项目任务书围绕“糖尿病认知障碍发病轨迹及基于方证相关的中药干预研究”等内容开展研究工作。目前已按项目任务书及项目年度调整计划完成全部研究工作。 .在项目执行之初，为确保评价的可靠性，课题组在前期研究工作基础上，首先根据DM大鼠主动性逃避反应不敏感的特征，确立了适合DM认知障碍的morris水迷宫方法和社交行为评价的行为学评价指标体系；同时进一步完善了认知障碍的个体化评价方法，首次建立了适合组间比较的认知能力评分方法。在此基础上进行了DM 认知障碍中医证候演变过程研究，首次建立了动物模型证候宏观（症状和体征）、微观（实验室检查）表征共表征模型动物证候，并以非靶标代谢组学获得的代谢表征验证并共同确立证候演变的时间节点的证候表征方法。确立了STZ诱导的DM模型中医证候特点。完成了基于非靶标代谢组学的DM 认知障碍代谢轮廓分析，确立了非靶标代谢组学在DM认知障碍代谢差异物分析中的地位和作用。完成了基于靶标代谢组学的DM 认知障碍生物标记物的时量关系研究，初步明确了DM 认知障碍不同阶段的代谢特征。完成了基于蛋白质组学的DM认知障碍生物标志物的研究，初步确立了5种差异蛋白。完成了海马神经元形态、突触可塑性的经时变化，确定了DM认知障碍大鼠认知能力时间相关性下降的神经生物学基础。完成了基于靶标代谢组学的 “方证相关”DM 认知障碍西洋参-石菖蒲及黄连-干姜干预研究。. 在国内外学术期刊发表研究论文 7篇；培养博士3人，硕士研究生 8人；授权发明专利 2 项。