脂联素线粒体稳态调节在糖尿病缺血心肌保护中的作用及关键分子机制

项目名称： 脂联素线粒体稳态调节在糖尿病缺血心肌保护中的作用及关键分子机制

项目编号： No.81470478

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： 陶凌

作者单位： 中国人民解放军第四军医大学

项目金额： 75万元

中文摘要： 申请者在国际上最早报道脂联素除代谢调节作用之外还具有直接心肌保护作用，且PPARγ依赖于脂联素发挥心脏保护作用。线粒体是细胞能量工厂及凋亡调节司令部。NO及PPAR协同激活子α(PGC-1α)通路是调控线粒体生物合成的主要系统。申请者与国外最新研究结果表明，脂联素既可刺激心脏eNOS/NO生成又可增加PGC-1α活性。糖尿病患者血浆脂联素降低，且心肌线粒体生物合成受损。因此，本课题力争阐明一条心肌保护通路的存在即脂联素通过NO/线粒体与PGC-1α/线粒体两大调控通路及其互调机制，促进线粒体生物合成，改善心肌能量代谢，抑制心肌细胞凋亡；试图验证一个科学假设的成立即2型糖尿病心肌脂联素/线粒体保护通路某个或多个环节受损，是糖尿病心肌对缺血损伤易感性增加的重要原因；进而明确一类干预措施的疗效即针对受损靶点的基因与药物干预，可能改善糖尿病心肌细胞能量代谢、抑制细胞凋亡、减轻心肌损伤。

中文关键词： 脂联素；线粒体生物合成；糖尿病；缺血性心脏病；心肌保护

英文摘要： Adiponectin (APN) is an adipocytokine secreted from adipose tissue. We demonstrated for the first time that APN exerts signi?cant cardiovascular protection against myocardial ischemia/reperfusion (MI/R) injury and that APN is also an indispensable molecule in PPARγ agonist cardioprotection following myocardial infarction. We and others have reported that APN not only stimulates the NO production but also increases the PGC-1α activity, both of which are critical for the mitochondrial biogenesis. Therefore, our present projects are via pharmacological, genetic intervention, in vivo and vitro animal models, 1) to unveil a new cardioprotective signaling pathway by which APN modulates the mitochondrial biogenesis via NO dependent pathway or/and PGC-1α dependent pathway to improve the energy metabolism, inhibit the apoptosis, 2) to verify a scientific hypothesis that the dysfunction of the APN/mitochondrial biogenesis signaling pathway results in the myocardial apoptosis and the impairments of myocardial energy metabolism, and ultimately sensitizes the diabetic heart to the ischemic injury, 3) finally to establish interventions on restoring the dysfunction of APN/mitochondrial biogenesis signaling, thus provide a new therapeutic strategy for the prevention and treatment of diabetic myocardial injury.

英文关键词： Adiponectin;Mitochondrial Biogenesis;Diabetes;Ischemic Heart Diseases;Cardioprotection