cTnIR193H突变致限制性心肌病心肌线粒体结构和功能紊乱的机制研究

限制性心肌病（RCM）是危害人类健康的严重心脏病，以心肌舒张功能障碍和间质纤维化为特征，预后差。心肌肌钙蛋白I（cTnI）突变是RCM主要病因之一，但致病机制不明。前期研究发现，cTnIR193H突变RCM小鼠存在心肌线粒体结构和功能损害，并早于舒张功能障碍的发生，且维持线粒体结构和功能稳定的基因ND5和促进其表达的转录因子LRPPRC过表达。因此提出科学假设：cTnIR193H突变经LRPPRC介导上调ND5过表达引起心肌线粒体结构和功能损害而促进RCM的发生和发展。我们将从动物和细胞层面，验证心肌线粒体结构和功能损害及能量代谢紊乱参与cTnIR193H突变导致RCM的发生发展；揭示cTnIR193H突变上调ND5过表达引起心肌线粒体结构和功能损害的作用；阐明cTnIR193H突变经LRPPRC介导调控ND5过表达的分子机制；为RCM靶向防治的转化医学研究提供重要的理论依据。

Primary restrictive cardiomyopathy (RCM) is a serious heart disease in human. It is characterized by myocardial diastolic dysfunction and its prognosis is poor. cTnI mutation is one of the main causes of RCM, but the pathogenesis is unknown. Our previous study found that the myocardial mitochondrial structure and function damage in cTnIR193H mutant RCM mice occurred preceding the overt symptoms of diastolic dysfunction. Furthermore the overexpression of ND5 gene that affects the mitochondrial structure and function and transcription factor LRPPRC which promoted ND5 expression has been observed. Therefore, in this study we propose a scientific hypothesis that LRPPRC mediates the ND5 overexpression, which causes damage to myocardial mitochondrial structure and function and promotes the development of diastolic dysfunction in cTnIR193H mutated RCM mice. We will investigate the roles of mitochondrial structure and function and energy metabolism in the development of diastolic dysfunction in cTnIR193H RCM mice. We will explore the mechanism underlying cTnIR193H mutation and the upregulation of ND5 expression in RCM myocardial cells. The data obtained from this study will provide us with important therapeutic basis for the treatment of diastolic dysfunction in the field of translational medicine and provide us with new clues for the treatment of single gene mutation caused cardiomyopathy.