支链氨基酸介导的能量代谢障碍在糖尿病心肌损伤中的作用及机制

代谢紊乱是心肌损伤的独立危险因素,但以糖、脂代谢为干预靶点的治疗措施效果不佳。我们前期研究证明,糖尿病动物出现以支链氨基酸(BCAA)堆积为特征的氨基酸代谢紊乱(Diabetes, 2015);而基因敲除所致BCAA代谢障碍动物继发全身糖脂代谢紊乱及器官损伤(EBioMedicine, 2016)。最新预实验发现，BCAA代谢紊乱小鼠心肌线粒体能量代谢调控关键分子丙酮酸脱氢酶(PDH)活性降低,缺血损伤加重。本课题结合基因干预模式动物与细胞分子手段,揭示PDH活性降低与BCAA代谢紊乱所致心肌损伤的因果关系;阐明PDH翻译后修饰与葡萄糖利用障碍能量代谢紊乱的内在联系; 确证切断糖脂与BCAA代谢紊乱互为因果的恶性循环及其导致的心肌能量代谢紊乱对糖尿病心肌的保护作用。为糖尿病心肌损伤提供新的分子机制，为从以干预BCAA代谢紊乱为切入点，预防和治疗糖尿病心肌代谢重构与心脏损伤提供新的治疗靶点。

Metabolic dysfunction is an independent risk factor for myocardial injury. However, numerous clinical studies have demonstrated glucose per se as a therapeutic target dose not improve the outcome in decreasing the cardiovascular complications. our recent studies have demonstrated that glucose-lipid metabolic disorder results in systemic BCAA catabolic disorders in obesity/diabetic mice (Diabetes, 2015); Conversely, BCAA catabolic disorders results in systemic glucose-lipid metabolic disorder(EBioMedicine, 2016). Surprisingly, our preliminary experimental results have clearly shown that chronic accumulation of BCAAs in a mouse model of impaired BCAA catabolism (PP2cm knockout) suppressed disrupted mitochondrial pyruvate utilization through inhibition of pyruvate dehydrogenase complex (PDH) activity and sensitized the heart to ischemic injury. Therefore, using pharmacological interventions and genetic animal models, our present project aims: 1) to reveal the causal link between BCAA related myopcadial injury and inhibition of PDH activity; if so, further to elucidate the molecular mechanisms by which posttranslational protein modification modulates the activity of PDH; 3) importantly, to explore effective pharmacological and genetic interventions to restore BCAA metabolism deregulation and metabolic dysfunction, thus providing a novel and promising therapeutic strategy for the prevention and treatment of metabolic disorder and myocardial injury in inviduals with T2DM.