肌浆网钙ATP酶小泛素化修饰对糖尿病降糖治疗时间窗口的影响研究

Of type 2 diabetes and pre-diabetes has been more than 200 million, but the proportion of early hypoglycemic therapy and the compliance rate is very low, a very important reason is not yet clear when hypoglycemic therapy can prevent or even reverse target organ damage development. Previous studies have shown that with the extension of the duration of diabetes, even if the blood sugar been controlled to normal, it still can not play the above roles. Diabetic hypoglycemic therapy is efficacious when it is used timely, but experimental evidence of its existence as well as the mechanism is not clear, the main reason is that it is difficult to evaluate the effect of hypoglycemic therapy. In our previous studies that we have used acute myocardial injury as the endpoint to evaluate of the effects of hypoglycemic therapy objectively and quantitatively. This application is intended to create two types of diabetes model on the basis of preliminary studies in the whole animal and cellular level, by using the new evaluation system, we can evaluate the effects of hypoglycemic therapy to make sure that there is really a valid time window for hypoglycemic therapy. For the first time we can verify the presence of metabolic memory phenomenon in diabetes, and then we can study whether it is related with epigenetics. This application, once implemented, will provided the experimental model for metabolic memory of diabetic myocardial damage, and to promote the early and individualized diagnosis and treatment of clinical diabetes.

我国2型糖尿病及其前期患者超过2亿，但早期降糖治疗的比例和达标率很低，一个很重要的原因是目前不清楚何时开始降糖治疗可以阻止，甚至逆转靶器官损害的发展。研究显示随着糖尿病病程的延长，强化降糖无益甚至有害。但国内外研究均未明确其存在的实验证据以及机制，主要原因是难以评价降糖治疗改善预后的效果。申请者曾以糖尿病急性心肌损伤耐受性为研究终点，应用新的系统客观、定量地评价降糖治疗效果。本申请拟在前期研究基础上，在整体动物和细胞水平建立两种糖尿病模型，初步探索长期糖尿病由于SERCA2a的小泛素化修饰途径关键位点ubc9、SUMO1和SERCA2a的DNA甲基化，抑制相应蛋白表达，导致降糖治疗不能通过调节其小泛素化修饰途径增加SERCA2a的表达和功能，从而改善其心肌损害。本申请完成后将为糖尿病代谢记忆研究提供实验依据，推动临床糖尿病的早期降糖治疗以及晚期联合新型药物（如去甲基化等）的综合治疗。