阿霉素（DOX）是高效、广谱的抗肿瘤药物，但因其心肌损伤性限制了临床应用。心脏阿霉素反应蛋白（CARP）是被DOX抑制的心脏特异性表达蛋白。我们前期研究发现，DOX给药的CARP敲除小鼠比野生型小鼠生存时间更短，生存率更低。此外，还发现CARP可以上调线粒体生成关键因子PGC-1α的表达，并抑制细胞凋亡相关转录因子TA p63γ的活性。因此我们推测：DOX下调CARP的表达，可能主要从两个途径引发心肌损伤：一方面降低了PGC-1α表达影响线粒体生成与功能，使活性氧无法有效清除造成了心肌氧化应激损伤；另一方面解除了对TA p63γ活性的抑制，诱导心肌细胞凋亡。本课题将利用CARP心脏特异性转基因及基因敲除小鼠，在动物、细胞及分子水平研究CARP对DOX心肌损伤的保护作用及机制。本研究将增进我们对DOX心肌损伤产生机制的理解，为防治DOX心肌损伤提供新的靶点和理论依据。

Doxorubicin (DOX; also known as adriamycin) is among the most effective and widely used anticancer drugs in the clinic. However, its clinical use is limited by the risk of myocaedial injury. Cardiac adriamycin responsive protein (CARP) is a heart specific protein, which expression is inhibited by DOX. Our preliminary data showed that the mortality was significantly increased and shorter survival time in CARP knockout (CARP-KO) mice compared to wild type (WT) mice. It also found that CARP increased peroxisome proliferator-activated receptor-γ coactivador-1α (PGC-1α) expression, the key regulator for mitochondrion biogenesis, and inhibited apoptosis-related transcription factor TA p63γ. Therefore, we speculate, DOX down-regulates CARP leading to reduced PGC-1α gene expression and liberates TA p63 γ, both of which result in increased cardiac damage. Decreased expression of PGC-1α exacerbates impairment of mitochondrial functions by augmenting oxidative stress in cardiac cells and increased activity of TA p63γ triggers apoptosis in myocardial cells. In this study, we used WT, transgenic cardiac-specific CARP overexpressing (CARP-TG) and CARP-KO mice, and the corresponding primary cultured cardiomyocytes to investigate the roles of CARP in cardiomyopathy induced by DOX. We will provide several lines of evidence indicating that CARP is the target for DOX-induced cardiac damage and a novel therapeutic strategy for DOX clinical applications based on the regulatory mechanisms of CARP expression.