GCN2抑制剂对糖尿病心肌病的保护作用及机制研究

糖尿病性心肌病是糖尿病主要并发症之一，严重危害患者健康。由于发病机理复杂，目前还没有治疗糖尿病心肌病的有效方法，寻找新的治疗药物备受关注。一般性阻遏蛋白激酶GCN2能够被氨基酸缺乏或其他应激条件所激活，从而参与多种生理和病理过程。我们之前发现，敲除GCN2能够通过减少脂毒性和氧化应激提高1型和2型糖尿病小鼠的心脏功能，但GCN2抑制剂能否用于糖尿病心肌病的防治还不清楚。本项目将在糖尿病小鼠模型中研究一种新型GCN2抑制剂（GCN2iB）对糖尿病心肌病的保护作用，并阐明GCN2iB对心肌胰岛素信号通路、能量代谢、氧化应激和细胞凋亡的影响。我们还将利用基因敲除小鼠，验证GCN2iB的心肌保护机制是否依赖于GCN2和Nrf2之间的相互作用。这些研究结果将为糖尿病性心肌病提供新的潜在药物。

Diabetic cardiomyopathy (DCM) is one of the major complications of diabetes and therefore a huge threat to diabetic patients. Due to its complicated pathogenesis, currently available therapies are far from ideal. Therefore, great efforts have been made to develop new therapy approaches for DCM. The eIF2α kinase general control nonderepressible 2 (GCN2) can be activated by amino acid starvation and other stress conditions, and can then play an important role in the physiological and pathological processes. Recently, we have demonstrated that GCN2 deficiency ameliorates cardiac dysfunction in diabetic mice by reducing lipotoxicity and oxidative stress. However, whether GCN2 inhibitors could protect against cardiac dysfunction in DCM remains unknown. In this project, a new GCN2 inhibitor (GCN2iB) will be used to treat diabetic mice and determine whether GCN2iB could ameliorate cardiac dysfunction, insulin resistance, metabolic disturbance, oxidative stress and apoptosis. Furthermore, we will also use GCN2 and Nrf2 KO diabetic mice to determine whether the protective effect of GCN2iB on DCM is dependent on GCN2/eIF2α pathway and GCN2-Nrf2 interaction. The results of this project will help us to develop new therapy approaches for DCM.