超过50%的肝硬化患者出现心脏结构与功能异常，被称为肝硬化性心肌病，主要症状包括心肌收缩与舒张功能减弱、心律失常、电生理异常等，发生机理尚未明确，也缺乏针对性的治疗手段。最新研究发现小鼠血清胆汁酸升高抑制心脏脂肪酸氧化水平而诱发肝硬化性心肌病，而胆汁酸合成酶ACOX2缺陷引起患儿肝脏纤维化和C27血清胆汁酸累积，结合申请人此前研究发现ACOX2突变与心脏脂肪酸氧化代谢酶的整体下调密切相关（PNAS 2017），推测ACOX2缺失或通过抑制脂肪酸氧化途径而引起心脏功能异常，最终导致肝硬化性心肌病。本项目拟建立人源Acox2突变敲入小鼠模型和原代心肌细胞培养体系，并结合我们现有的基因敲除模型及合作单位提供的cTnI小鼠心肌病模型，针对血清胆汁酸、心脏结构与功能及脂肪酸氧化进行整合基因组功能研究。本项目将深入阐述ACOX2突变诱发肝硬化性心肌病的分子机制，为该病的临床诊断和研发治疗提供重要线索。

More than 50% of cirrhotic patients have cardiac structure and function abnormalities, termed as cirrhotic cardiomyopathy (CMP). The major symptoms include diminished myocardial systolic and diastolic function, arrhythmia, electrophysiological abnormalities. The pathogenesis of the CMP has not been explained, there is a lack of targeted treatment. Recent studies found that excess serum bile acids cause CMP via inhibiting the myocardial fatty acid oxidation. Meanwhile, genetic variations in bile acid synthase ACOX2 lead to the accumulation of C27 bile acid intermediates and liver fibrosis in children. Our previous data indicates that ACOX2 mutation is closely related with decreased myocardial fatty acid oxidation pathway (PNAS 2017). We assumed that ACOX2 depletion might induce CMP due to dysregulated bile acid metabolism. In this study, we construct Acox2 point mutation knock-in animal model and perform primary myocardial cell culture, combined with our Acox2 knockout model and cTnI cardiomyopathy model provided by project partner, which launched integrated genomic studies on serum bile acids, cardiac systolic function and fatty acid oxidation changes in Acox2 mutant mice. This study will further clarify the mechanisms of ACOX2 variations on the induction of cirrhotic cardiomyopathy, and provide critical clues for clinical diagnosis of CPM and establish effective therapeutic strategies.