心肌肥厚是心脏对压力负荷的适应性反应，以心肌细胞蛋白质合成的增加和细胞体积的增大为主要特征，是引起多种心血管疾病的重要危险因素之一。真核翻译起始因子4E结合蛋白4E-BP1能够通过抑制帽子依赖方式翻译起始复合物的组装而抑制蛋白合成。我们在前期研究中发现敲除4E-BP1可以明显改善压力超负荷导致的心肌纤维化和功能失常，但4E-BP1如何影响心肌肥厚和心力衰竭的具体分子机制还不清楚。本项目将利用4E-BP1基因敲除小鼠以及腺病毒转染和基因沉默技术，在动物和细胞层面研究4E-BP1对心力衰竭的调控作用，阐明4E-BP1对心肌肥厚信号通路、纤维化、线粒体生物合成和能量代谢、细胞凋亡的作用，并进一步探讨4E-BP1对靶基因IRF-7和SERCA2a的翻译调控作用的分子机制，为心力衰竭的临床治疗提供新的靶点和理论依据。

Cardiac hypertrophy is an adaptive response to pressure or volume stress, which is characterized by an increase in cell size and enhanced protein synthesis. It is one of the most important risk factors for most cardiovascular disease. Eukaryotic translation initiation factor 4E binding protein 1(4E-BP1) is a protein synthesis repressor though inhibiting the assembly of cap-dependent translation initiation machinery. Our preliminary studies demonstrated that 4E-BP1 knockout profoundly attenuated the cardiac fibrosis and dysfunction induced by pressure overload, however, the effects of 4E-BP1 on the cardiac response to stress and the development of congestive heart failure are totally unknown. In order to determine the role of 4E-BP1 in cardiac hypertrophy and heart failure, in this project we will use 4E-BP1 knockout mice, adenovirus vector and siRNA method to study the modulation effects of 4E-BP1 on heart failure, illuminate the effects of 4E-BP1 on cardiac hypertrophy signaling pathways, fibrosis, mitochondrial biogenesis, energy metabolism and cell apoptosis, and further explore the detail mechanism of how 4E-BP1 regulate the translation initiation of its target genes IRF-7 and SERCA2a. Our data will reveal the role of 4E-BP1 in cardiac hypertrophy and provide a novel therapeutic approach for treating congestive heart failure.