新型携氧载体Hp-HbNPs改善糖尿病心肌对缺血再灌注损伤敏感的线粒体SIRT3机制研究

项目名称： 新型携氧载体Hp-HbNPs改善糖尿病心肌对缺血再灌注损伤敏感的线粒体SIRT3机制研究

项目编号： No.81471042

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李涛

作者单位： 四川大学

项目金额： 73万元

中文摘要： 糖尿病是心血管疾病主要的危险因素之一。糖尿病患者由于氧化应激、胰岛素抵抗以及一系列代谢综合征，导致心肌对缺血再灌注（I/R）损伤的敏感性增高。这种心肌I/R敏化是糖尿病患者心肌缺血事件高发病率和高死亡率的重要原因，并且削弱了传统心肌保护措施的效能。基于前期研究基础，本申请将制备一种新的糖尿病心肌保护药物- - 结合珠蛋白优化的新型血红蛋白类携氧载体Hp-HbNPs。在保证其良好组织灌注和氧供前提下，验证其可降低糖尿病心肌I/R损伤敏感性，发挥糖尿病心肌保护作用。并且，机制学研究将揭示线粒体去乙酰化酶SIRT3是介导上述保护作用的关键靶点，证实抑制线粒体氧化应激，改善胰岛素抵抗以及维持线粒体钙稳态是Hp-HbNPs减轻糖尿病心肌I/R损伤的主要保护环节。该课题的顺利实施，不仅可以获得一种更安全有效、更有临床应用前景的新型血红蛋白类携氧载体，还将为临床糖尿病心肌保护提供新的思路和药物作用靶点。

中文关键词： 糖尿病心肌病；缺血再灌注损伤；氧化应激；线粒体；胰岛素抵抗

英文摘要： Diabetes mellitus is one of the major risk factors for cardiovascular disease. Because of oxidative stress, insulin resistance and a series of metabolic syndrome, the diabetic heart is more sensitive to ischemia/reperfusion (I/R) injury. The consequences include that the morbility and mortality of ischemic heart disease in diabetic patients are much higher as compared to non-diabetic patients, and the effects of traditional cardioprotective strategies on diabetic heart are less effective or even invalid. In this application, we will produce a new protective agent for diabetic heart- - haptoglobin modified novel hemoglobin based oxygen carrier Hp-HbNPs. Based on its excellent tissue perfusion and oxygen supply capacity, we will prove its efficacy on reducing sensitivity of diabetic heart to I/R injury by a series of in vivo and in vitro studies. Moreover, this study will demonstrate that attenuation of mitochondrial oxidative stress, amelioration of insulin resistance and maintenance of mitochondrial calcium homeostasis are the major pathways to enhance defence during I/R injury, and reveal that mitochondrial SIRT3 is the key therapeutic target to initiate these protective effects. Therefore, this study will not only bring us a more safe, more effective and more clinically promising hemoglobin based oxygen carrier, but also provide new thought and novel therapeutic target for diabetic heart protection in clinical situation.

英文关键词： Diabetic cardiomyopathy;Ischemia/reperfusion injury;Oxidative stress;Mitochondria;Insulin resistance