Contactin-2通过调控转录因子NUPR1在心力衰竭与心脏重构中的作用及机制研究

心衰的治疗是临床难点。改善心脏重构是心衰治疗的研究热点，新的有效的治疗靶点仍有待探究。Contactin-2(CNTN2)在心衰中的表达改变与功能尚未阐明。预实验证实，心衰时心肌细胞CNTN2表达显著下调，CNTN2敲除小鼠杂合子构建心衰模型后，心功能恶化与心脏重构较野生型小鼠更加显著，提示CNTN2在心衰发展中发挥关键作用。转录组测序结果提示，NUPR1可能是CNTN2发挥作用所调控的下游分子。NUPR1可抑制细胞铁死亡。因此提出假设：心肌细胞CNTN2通过调控NUPR1抑制心肌细胞铁死亡，从而减轻心衰与心脏重构。本项目拟进行动物与细胞实验探究：1)CNTN2在心衰与心脏重构中的作用；2)CNTN2通过调控NUPR1在心肌细胞铁死亡与心衰中的作用及机制；3)增加CNTN2表达对心衰的保护作用。本项目成果将阐明CNTN2在心衰与心脏重构中的作用及机制，为心衰防治提供新策略。

The treatment of heart failure is a difficulty in clinical practice. To ameliorate cardiac remodeling is a research focus in the treatment of heart failure, and new effective therapeutic targets still need to be discovered. The expression change and function of Contactin-2 (CNTN2) in heart failure have not been demonstrated yet. Our preliminary experiments confirmed that the expression of CNTN2 in cardiomyocytes was significantly down-regulated during heart failure. The heart failure model was performed on mice, the deterioration of heart function and cardiac remodeling were more significant in CNTN2 knockout heterozygotes mice than those of wild type mice, suggesting that CNTN2 plays a key role in the development of heart failure. Results of RNA sequencing indicated that NUPR1 could be the downstream molecule regulated by CNTN2. NUPR1 can inhibit ferroptosis. Therefore, we hypothesize that CNTN2 regulates NUPR1 and inhibits the ferroptosis of cardiomyocyte, thereby attenuating heart failure and cardiac remodeling. This project will perform animal and cell experiments to investigate: 1) the role of CNTN2 in heart failure and cardiac remodeling; 2) the role and mechanism of CNTN2 in cardiomyocyte ferroptosis and heart failure via regulating NUPR1; 3) the protective effects of over-expressing CNTN2 on heart failure. The results of this project will clarify the role and mechanism of CNTN2 in heart failure and cardiac remodeling, and provide new strategies for the prevention and treatment of heart failure.