蛋白质合成异常增加是心肌肥厚形成的主要机制。泛素化是调节蛋白质功能和信号传递的一个重要过程。我们既往研究证实连接酶(E3)介导的蛋白泛素化在心肌肥厚中起重要作用。我们前期实验发现压力负荷因素可激活心脏中mTOR信号通路和泛素-蛋白酶体系统(UPS); 但是UPS激活如何节负向蛋白泛素化和降解，激活PI3K/AKT/mTOR、ERK等信号、导致心肌肥厚等问题尚不清楚。本课题将利用心脏过表达或基因敲除小鼠及培养的心肌细胞，拟阐明：(1) 压力负荷因素增高泛素加工酶表达和活性的分子机制; (2) 泛素活化酶UBA1激活泛素、E3连接酶Cullin,等识别和促进AT1受体结合相关蛋白泛素化及调节下游PI3K/AKT/mTOR、ERK等信号通路的机制; (3) 去泛素酶Uchl1和Otud1终止底物蛋白泛素化的机理; (4) 泛素化的蛋白底物被免疫蛋白酶体降解的机制；最后明确泛素修饰引起PI3K/AKT/mTOR、ERK等激活，导致心肌肥厚形成的病理机制，最终为心肌肥厚的早期诊断和预防提供新的潜在靶点。

Increased protein synthesis plays the major role in the development of cardiac hypertrophy. Ubiquitnation play a critical role in regulating protein function and signaling transduction. Our previous studies confirmed that ubiquitin E3 ligase-mediated protein ubiquitination and degradation inhibits cardiac hypertrophy. Our preliminary studies suggested that angiotensin (Ang) II infusion and TAC cause activation of PI3K/AKT/mTOR,ERK signaling and Ubiquitin-proteasome system (UPS), including the increased expression of ubiquitin activating enzyme (UBA1), E3 ligase (Cullin family and others) and deubiquitinases (Uchl1 and Otud1) and proteasome; however, the effects of UPS activation on the ubiquitination and degradation of target substrates (PI3K/AKT/mTOR, ERK regulators) and the cardiac hypertrophy remain unclear. In the present study, we will use knockout or cardiac transgenic mice and in vitro cultured cardiomyocytes, and investigate the molecular mechanisms by which pressure overload regulates the expression or activity of UPS; how does UBA1 activate ubiqutin, Cullins interact with and ubiquitinate regulators of mTOR, Uchl1 and Otud1 remove the ubiquitin from their substrates; ubiquitn-modified proteins are degradated by proteasome. Finally, the present study will demonstrate the important role of Tubiquitination-mediated PI3K/AKT/mTOR, ERK activation on cardiac hypertrophy, and provide novel molecular insights into the pathogenesis of cardiac hypertrophy.