胞浆蛋白始发性抑制因子GEFT在心肌肥厚中的作用

Pathological cardiac hypotrophy always ends up with heart failure. However, the molecular mechanism that underlies this process and the primary cause of hypertrophy remain unknown. Therefore, we proposed a theory that endogenous inhibitors which are highly expressed in adult heart are the originating factors that resist the occurrence of cardiac hypertrophy and identified a class of candidate originating factors. After the study of Lrrc10, a nuclear protein originating factor, is completed, we carry on the study of Geft which is a cytoplasmic protein originating factor. Although the in vitro roles of Geft in many cellular processes are well documented, the in vivo role of Geft in heart remains absolutely unknown on account of the lack of genetically modified animal models. Thus, we generated a cardiac specific Geft knockout mouse for the first time. Preliminary results indicated that knockout mice are more susceptive in response toβadrenergic stimuli，which suggesting its protective role in cardiac hypertrophy. In this study, we attempt to test the function and mechanism of action of Geft in response to hypotrophy stmuli, elucidate the function of Geft in pathological cardiac remodeling, reveal the molecular mechanism of cytoplasmic protein originating factors in myocardial hypotrophy using knockout mice, and provide theory basis for the development of clinical drugs for cardiovascular disease treatments.

病理性心肌肥厚往往是以心力衰为结果。而心肌肥厚的始发性因素及内在分子机制至今不明。为此，我们提出成体心脏中高表达的抑制因子是抵御心肌肥厚疾病发生的始发性因子的理论，并筛选到一批始发性候选基因，在完成对核蛋白始发性因子Lrrc10研究后，进一步展开对胞浆蛋白始发性因子Geft的研究。尽管Geft体外细胞生物学功能已经被广泛报道, 但由于缺乏遗传学修饰的动物模型，其在体内心脏中的功能至今一无所知。鉴此，我们率先获得了心脏中特异性敲除Geft的小鼠，初步证明心脏缺失Geft小鼠敏感于β肾上腺素诱发的心肌肥厚。本研究拟利用敲除小鼠模型，探讨Geft在心肌细胞效应于肥大刺激的下游效应分子及其作用机制，以阐明Geft在心肌病理重构中的作用，揭示胞浆蛋白始发性因子在心肌肥厚中的分子机制，为临床开发治疗心血管药物提供理论依据。

病理性心肌肥厚往往是以心力衰竭作为为结果，而心肌肥厚的始发性因素及内在分子机制至今不明。为此，我们展开对胞浆蛋白始发性因子Geft的研究。在此项研究中，我们探讨了Geft在心肌细胞效应于肥大刺激的下游效应分子及其作用机制，阐明了Geft在心肌病理重构中的作用，揭示了胞浆蛋白始发性因子在心肌肥厚中的分子机制，为临床开发治疗心血管药物提供理论依据。其具体的结果如下：（1）证实了GEFT作为一个心脏内源性的保护因子，在病理刺激下抵制心肌肥厚；（2）证明GEFT通过CDC42发挥对心肌肥厚的保护作用；（3）证明了心脏中与GEFT互作的因子BVES同样发挥抵制心肌肥厚的功能；（4）表明GEFT与BVES协同抑制心肌肥厚的发生；（5）发现CDC4介导了GEFT与BVES协同抑制心肌肥厚的作用；（6）体内证明BVES依赖于GEFT发挥对心脏的保护作用。（7）课题共已发表标注SCI论文6篇，另有一篇SCI论文已经接受；（8）课题共培养博士研究生1人，硕士研究生10人。