TRUSS在病理性心肌肥厚中的功能和机制研究

Pathological cardiac hypertrophy, the leading cause of heart failure, is a multifaceted process that is regulated by a complex molecular network. Despite accumulating studies, the underlying mechanisms of this process is far away from fully understood. Ubiquitylation is one of the most important types of protein posttranslational modification, and has been reported to be closely involved in pathologic cardiac hypertrophy via its capacity to mediate protein localization, activation, degradation, etc. As a ubiquitin E3 ligase, TRUSS holds an ability on regulating innate immune signaling and Ca2+ pathway, which process pivotally regulatory effects on cardiac hypertrophy. However, the role of TRUSS in cardiac hypertrophy is unknown. Our preliminary experiments exhibited a significantly upregulated expression of TRUSS in hypertrophied heart samples compared to normal controls, suggesting a potential involvement of TRUSS in cardiac hypertrophy. In this project, we aimed to demonstrate the regulatory effect of TRUSS on cardiac hypertrophy and to clarify the underlying mechanism, which will be completed based on substantial experiments using cardiomyocyte-specific TRUSS-knockout or transgenic mice as well as high throughput screening technology. The outcomes of this project will provide new avenues for the treatment of cardiac hypertrophy and the related heart diseases.

心肌肥厚是心力衰竭的重要病理过程之一，受细胞内复杂信号通路调控。阐明心肌肥厚的分子机理对于预防和治疗心力衰竭具有重要意义。泛素化是细胞内蛋白质翻译后修饰的重要类型，通过改变蛋白质的定位、激活和降解等功能，参与心肌肥厚相关信号通路调控。泛素连接酶功能的TRUSS在心肌肥厚相关的天然免疫信号通路及细胞内Ca2+离子调节上有重要功能。然而，目前国内外对于TRUSS在心血管系统中的作用和机制尚无报道。我们前期初步研究显示，TRUSS在心肌肥厚病人和小鼠心脏组织中高表达，并对压力超负荷引起的心肌肥厚有重要影响。本项目拟通过心肌细胞特异敲除和过表达TRUSS的基因工程小鼠模型，结合高通量筛选技术，系统地阐明TRUSS在病理性心肌肥厚中的功能和作用机制。以期为心肌肥厚临床药物开发提供新靶点和新策略。

泛素连接酶TRUSS在心肌肥厚相关的天然免疫信号通路及细胞内Ca2+离子调节上有重要功能。然而，TRUSS在心肌肥厚中的作用仍有待研究。本项目发现TRUSS在病理性心肌肥厚发生过程中上调表达，证实了心肌细胞特异性TRUSS过表达促进压力超负荷和激动剂诱导的心肌肥厚，而心肌细胞特异性TRUSS缺失则减缓小鼠在该模型下心肌肥厚的发生。对TRUSS调控心肌肥厚分子机制的研究发现，TRUSS可促进IκBα泛素化依赖的降解，进而激活IκBα相关信号通路。通过体内过表达位点失活型IκBα的逆转实验验证了TRUSS通过IκBα调控心肌肥厚的作用机制。本项目研究明确了TRUSS对病理性心肌肥厚的关键生物学功能，阐明了TRUSS调控心肌肥厚的分子机制。