心肌重构是诱发心力衰竭的主要原因。然而，目前最佳的临床药物治疗仍不能完全逆转心肌重构，阻断心衰的发展。基于我们发现去泛素化酶BRCC36在心肌重构中发挥的重要作用，提出假说：通过开发BRCC36新型抑制剂，抑制NLRP3炎症小体激活，可改善梗死后炎症引发的心肌重构，预防心衰发生；通过开发BRCC36新型激动剂，对TGF-β/Smad通路负性调控，可改善慢性压力负荷引发的心肌纤维化和重构。目前特异性靶向BRCC36的药物尚未有报道。本项目运用计算机辅助的药物筛选技术，以BRCC36为新型药物治疗靶标，试图1）利用人工智能AI药物筛选技术开发BRCC36新型抑制剂/激动剂，并研究作用机制；2）在细胞和动物水平分别研究BRCC36新型抑制剂对梗死后炎症引发的心肌重构的治疗效果，以及新型激动剂对慢性压力负荷引发的心肌纤维化和重构的治疗效果。这些研究结果有望为心衰患者提供新的临床潜力药物。

Myocardial remodeling is a major cause of heart failure. However, the current clinical drug treatment cannot completely reverse myocardial remodeling and block the development of heart failure. Recently, we discovered that the deubiquitinating enzyme BRCC36 played an important role in myocardial remodeling. Thus, a hypothesis is put forward: it is crucial to develop a novel BRCC36 antagonist to inhibit the activation of NLRP3 inflammasome, thereby ameliorating adverse ventricular remodeling caused by inflammation after post-myocardial infarction; it is crucial to develop a novel BRCC36 agonist to inhibit the TGF-β/Smad signaling pathway, thereby ameliorating cardiac fibrosis and ventricular remodeling caused by chronic pressure overload. Up to now, specific pharmacological antagonist or agonist of BRCC36 has not been reported. In this study, the computer-aided drug screening was applied, using deubiquitinating enzyme BRCC36 as a drug target. We attempted to 1) use artificial intelligence to design a novel BRCC36 antagonist/agonist and study the mechanism of action; 2) use single cell and animal level approaches to study the effects of BRCC36 antagonist on ventricular remodeling induced by inflammation and effects of BRCC36 agonists on cardiac fibrosis and ventricular remodeling induced by chronic pressure overload. The results may provide new potential drugs for clinical treatment of heart failure patients.