MYH6 p.D629N突变引起肌球蛋白功能构象失调导致心肌铁死亡在原发性心房心肌病中的致病作用与机制研究

原发性心房心肌病是一类新的心肌病亚型，但其致病机制尚不清楚。.前期我们对16组疾病家系进行了基因测序，发现其中3个家系存在MYH6基因(编码心房心肌细胞特有的肌球蛋白重链)突变；近期我们构建了基因编辑鼠及iPSC细胞模型，初步探究发现：MYH6 p.D629N突变可显著增加心肌细胞铁死亡。为此，我们提出假说：MYH6 p.D629N突变→肌球蛋白动态构像失调→能量代谢↑→激活ROS/HMOX1↑→铁离子↑→心房心肌铁死亡，详细机制值得深入探讨。.本项目拟研究：①MYH6点突变导致肌球蛋白构象失调及其影响心房心肌细胞能量代谢的机制；②心房心肌细胞能量代谢异常导致ROS/HMOX1上调、铁离子蓄积，引起心房心肌细胞铁死亡，进而导致心房心肌病的分子机制；③ROS/HMOX1靶向药物的筛选(基于计算机辅助药物设计)及其治疗效果评估。旨在：阐明原发性心房心肌病的致病机制，为其治疗提供潜在靶点。

Primary atrial cardiomyopathy, as a novel subtype of cardiomyopathy, is lacking in studies on the molecular mechanisms..Previously, we collected 16 pedigrees with atrial cardiomyopathy and underwent whole exome sequencing (WES), screening out 3 of them with MYH6 mutations. We built iPSC-ACMs cell line and CRISPR/Cas9 murine models to investigate the pathogenicity of MYH6 p.D629N, a mutation located in S1 domain of the myosin heavy chain α. The preliminary work revealed that MYH6 p.D629N can lead to the ferroptosis of atrial cardiomyocytes. We hypothesized that: MYH6 p.D629N mutation → dynamic conformational changes of myosin → ROS/HMOX1↑ → ferroptosis of atrial cardiomyocytes → primary atrial cardiomyopathy..The present study is intended to investigate:.1. The metabolic remodeling of atrial cardiomyocytes with MYH6 p.D629N mutation;.2. The molecular mechanism underlying the disturbance of energy metabolism leading to ROS/HMOX1 upregulation, iron deposition, and ferroptosis in atrial cardiomyocytes;.3. Chemical screening and new drug evaluation targeting on ROS/HMOX1 based on computer aided drug design..The present project focuses on the mechanisms underlying atrial cardiomyopathy, aiming to develop the personalized therapeutic strategy.