近期证据显示能源代谢异常对心力衰竭和左室重构的发生发展起重要作用，但其具体作用和分子机制尚不清楚。我们的前期研究发现Acot1, 一种参与脂肪酸代谢的酶，在糖尿病小鼠心肌组织中表达显著增高并可通过PGC-1α／PPARs途径介导的脂肪酸氧化减低以及线粒体功能改善，防止或改善糖尿病小鼠的心肌功能障碍。本项目将在此基础上，建立Acot1心脏特异性转基因小鼠和Acot1心脏特异性基因敲除小鼠，并以此为研究模型，探讨Acot1 对心脏能源底物代谢（脂肪酸和葡萄糖代谢）、线粒体生物合成与线粒体功能、以及最终对心肌功能的影响，阐述心肌细胞能源代谢与心力衰竭之间的关系，并对其分子信号转导机制进行研究。这一研究对于阐明心衰时心肌细胞能源代谢紊乱的机制及其与心脏功能衰竭间的关系具有重要意义，并可为心力衰竭的代谢治疗发现新的分子干预靶点提供理论依据。

There is emerging evidence showing that the disturbances in myocardial substrate metabolism contribute to the progression of left ventricular remodeling and to heart failure. However, the impact of myocardial substrate metabolism on ventricular contractile function and the underlying molecular mechanisms are poorly understood. Our previous study revealed that Acot1, a gene involved in fatty acid metabolism, is highly up-regulated in the heart of db/db mice by using global gene expression analysis and obtained evidence to support the concept that Acot1 may have protective effects on cardiac dysfunction in the diabetic heart via PGC1α/PPARα signaling pathway. To continue our study, we plan to generate cardiac specific Acot1-deficient mice and mice with cardiac specific overexpression of Acot1. By using these gene-modified mice, we will investigate the role of Acot1 in myocardial substrate(fatty acid and carbohydrate) metabolism, in mitocondrial biogenesis and function, and in cardiac function. We will characterize the abnormalities of subatrate metabolism and mitocondrial dysfunction occurred in these mice, and importantly the impact they have on left ventricular function and the underlying molecular mechanisms or signaling pathways. We believe that our study will help us understand the mechanism of metabolic abnormanilies occurred in heart failure and the consequences of these metabolic changes on heart function, which will provide basis for generating novel therapeutic target by manipulation of cardiac energy metabolism in heart failure.