心肌纤维化是多种心脏疾病恶性演进的共同病理基础，对抗或逆转纤维化的发生是有效降低心脏疾病死亡率的重要研究方向。各种病理因素诱发的心肌细胞死亡是纤维化发生的始动机制。近期研究证实，过度自噬激活是心肌细胞死亡的直接病理基础，但其发生机制尚未阐明。本室前期研究发现，CREG是成熟心肌细胞中高表达的溶酶体稳态调控因子，其表达减少引起心肌细胞自噬激活和心肌纤维化发生。本研究尝试从心肌细胞内稳态调控入手，通过CREG低表达的杂合子小鼠和原代心肌细胞两种模型，阐明CREG在心肌自噬死亡和纤维化发生中的作用及机制；并通过心肌特异性过表达CREG的转基因小鼠对抗心肌纤维化的治疗研究，揭示CREG调控心肌细胞自噬-溶酶体稳态、保护心肌存活、对抗纤维化发生的作用机制。期望本研究的顺利完成，能深入揭示以CREG为代表的自噬-溶酶体调控分子在心肌细胞损伤和纤维化发生中的作用，为心脏疾病防治提供新思路。

Cardiac fibrosis is a common feature of end-stage heart diseases, independently of their etiologies, and the leading cause of morbidity and mortality in our country. Loss of cardiomyocytes due to apoptosis, necrosis, and/or autophagic-associated cell death is a key initiating mechanism of cardiac fibrosis. Autophagy is an intracellular lysosomal degradation process operating in homeostatic clearance of organelles and protein aggregates. However, pressure overload and stress elicit a robust autophagic response and lead to the death of cardiomyocytes, although the underlying mechanisms remain poorly understood. Cellular Repressor of E1A-stimulated Genes (CREG) is an evolutionarily conserved glycoprotein that promotes cell differentiation and homeostasis in response to stress and damage. Our preliminary studies demonstrated that CREG is highly expressing in embryonic and adult myocardium. Moreover, reduced CREG expression in CREG heterozygous (CREG+/-) mice enhances cardiac fibrosis during aging or after angiotensin II treatment, correlating with increased autophagic activities in cardiomyocytes. Base on these findings, we hypothesize that suppression of CREG expression might contribute to cardiomyocyte death and cardiac fibrosis by activating the autophagic-lysosomal pathway. To test this hypothesis, we propose the following aims: 1) To explore the relationship of reduced CREG expression and autophagic associated cardiomyocyte death and cardiac fibrosis using CREG+/- mice; 2) CREG loss of function analysis will be performed in primary culture cardiomyocytes to determine the mechanisms that CREG regulates autophagic-associated cardiomyocyte death; 3)Using cardiomyocyte- specific CREG transgenic mice to investigate the effect of CREG overexpression on angiotensin-induced autophagic activation, cardiomyocyte injury and cardiac fibrosis. Completion of the proposed experiments will provide new insights into the mechanisms whereby CREG antagonizes cardiomyocyte death and cardiac fibrosis by modulating the autophagic-lysosomal activity. It may also be implicated in the development of new therapeutic approaches.