基于芯片技术开展基础与临床比较探讨丹蛭降糖胶囊精准治疗糖尿病大血管病变的研究

Macrovascular complications of type 2 diabetes lead to increased mortality of cardiovascular and cerebrovascular events. Previous studies have shown that carotid intima-media thickness of Danzhijiangtang Capsule could reduce the patients and animal, the expected delay of cardiovascular events. Concise scientific questions, put forward through a comparative study of animal experiment and clinical observation of the effect of Danzhijiangtang Capsule, clear a same related genes and pathways play a protective vascular disease hypothesis. This topic is in the KKAy mice and macroangiopathy in type 2 diabetes as the research object, in order to find related genes and pathways are the same as the starting point, in the preparation of traditional Chinese medicine clinical curative effect of the treatment of diabetic macrovascular disease is as a means of intervention using miRNA microarray and ILLUMINA human genome SNP chip and other modern biological technology the intervention effect and mechanism of Danzhijiangtang Capsule in the treatment of diabetic macrovascular disease, provide the basis for clinical application of precision, also provide a new mode of accurate treatment research.

2型糖尿病大血管病变导致心脑血管事件死亡率激增。前期研究显示丹蛭降糖胶囊能减少患者及动物的颈动脉内膜中层厚度，预期延缓心脑血管事件的发生。凝练了科学问题，提出通过动物实验及临床观察，明确丹蛭降糖胶囊影响的相关基因功能及通路而发挥保护血管病变的假说。本课题以KKAy小鼠及2型糖尿病大血管病变为研究对象，以寻找被影响的相关基因功能及通路为切入点，以治疗糖尿病大血管病变确有临床疗效的中药制剂为干预手段，采用miRNA表达谱芯片、ILLUMINA人类全基因组SNP芯片等现代生物学技术，探讨丹蛭降糖胶囊治疗糖尿病大血管病变的干预作用及机制，筛选适合使用丹蛭降糖胶囊的研究对象，为临床精准应用提供依据，亦为精准治疗研究提供新的模式。

2型糖尿病大血管病变导致心脑血管事件死亡率激增。前期研究显示丹蛭降糖胶囊能预期延缓心脑血管事件的发生。本课题通过动物实验及临床研究，基于丹蛭降糖胶囊可减轻大鼠主动脉组织损伤程度，采用测序技术及相关生物信息学分析方法，研究糖尿病大血管病变模型大鼠与正常大鼠以及丹蛭降糖胶囊干预后的主动脉组织中mRNA和LncRNA的差异表达，与模型组相比，丹蛭降糖胶囊组中上调mRNAs表达1728个，下调mRNAs表达2490个。筛选糖尿病大血管病变模型大鼠发病过程中关键lncRNAs，发现共表达的差异基因共16个，预测Kantr潜在共同互作的10个miRNAs，其中miR-666-3p、miR-383-3p、miR-296-3p、miR-145-5p、miR-23a-5p具有较好保守性，为寻找糖尿病发病过程中的潜在标记物与中医药作用靶点提供依据。开展丹蛭降糖胶囊干预糖尿病大血管病变患者的临床研究，治疗12个月后，治疗组和对照组中医证候疗效分别为82.1%和74.5%，治疗组和对照组HbA1c水平分别显着降低0.59±0.50%和0.26±0.95%，低密度脂蛋白水平显着降低0.76±1.10 mmol/L和0.35±0.98 mmol/L，治疗组和对照组颈动脉内中膜厚度分别显着减少0.03±0.02 cm和0.02±0.01 cm，均具有统计学差异。并建立中药复方治疗糖尿病大血管病变的RCT数据库，系统性评价益气养阴活血法治疗糖尿病大血管病变随机对照试验疗效、安全性评价及对相关临床结局的影响，为中药治疗大血管病变提供疗效和安全性证据，并将通过基因测序为临床精准应用丹蛭降糖胶囊提供依据。