心力衰竭是多种心血管疾病的最终转归，临床机制复杂，而代谢重构是心衰发生发展的关键因素。多项研究表明Pdk1缺失导致心衰，申请人应用基于1H NMR的代谢组学已证实心肌细胞特异敲除Pdk1的小鼠心脏代谢轮廓紊乱，但分子机制有待更为详实的阐明。我们通过多元统计明确牛磺酸对Pdk1缺失导致的差异代谢模式起主要贡献，添加牛磺酸能部分逆转沉默Pdk1所引起的细胞凋亡和氧化应激，Pdk1调控牛磺酸转运体Taut的表达。此外，我们发现Pdk1可调控Klf14的表达，而Klf14是Taut潜在的转录因子。本项目拟应用核磁共振波谱和多元统计阐明代谢轮廓；在细胞和动物水平，通过外源给予牛磺酸或改变Taut表达，进一步验证Pdk1通过调控Taut影响心肌细胞牛磺酸的胞内转运；通过ChIP明确Klf14与Taut启动子区域的结合，探究Pdk1调控Taut表达的分子机制。本项目有望揭示心力衰竭发生发展的新机制。

Heart failure (HF) is a progressive, complex, end-stage disease condition of all maladies of the heart. There is evidence suggesting that metabolic remodeling plays a major role in heart failure. Many researches have shown that disruption of Pdk1 caused severe and lethal heart failure. Metabolomic results showed the abnormal cardiac metabolome in Pdk1 KO mice, but its potential mechanism remains unclear. Multivariate analysis revealed that taurine is the major contributor to the abnormal metabolism. Furthermore, supplementary of taurine could rescue the apoptosis and oxidative stress caused by Pdk1 deficiency. We also found Pdk1 can regulate the expression of Taut and Klf14. The aim of this study was to explore metabolic pattern in Pdk1 KO mice using 1H NMR-based metabolomics. Moreover, the role of Pdk1 mediated cardiac taurine metabolic remodeling will be investigated in vivo and in vitro. This project is expected to provide new mechanisms in the pathogenesis of HF.