FoxO3/Mst1介导的心肌细胞脂毒性在2型糖尿病心肌病中的作用及分子机制

“脂毒性”引起心肌细胞损伤，心脏纤维化和心脏功能减低，是2型糖尿病心肌病的重要病理基础，其发病机制不明。课题组在国家自然科学基金资助下发现，哺乳动物STE20样激酶1（Mst1）在“糖毒性”及1型糖尿病心肌病中发挥关键作用。然而，Mst1是否介导2型糖尿病“脂毒性”诱发的心肌损伤？目前尚不清楚。进一步研究发现，在2型糖尿病状态下，“脂毒性”可能通过促进转录因子FoxO3与Mst1基因启动子直接结合，上调Mst1蛋白表达，继而诱发心肌损伤。然而，Mst1如何介导2型糖尿病心肌病心脏舒张及收缩功能障碍？其分子机制如何？仍需研究阐明。本课题组针对以上问题，拟从基因转录，蛋白表达，蛋白翻译后修饰层面揭示“脂毒性”调控FoxO3/Mst1信号通路，加剧2型糖尿病心肌病的具体分子机制。本项目的成功实施可能阐明2型糖尿病心肌病发生发展的关键分子机制，为降低此类患者的心源性死亡率提供理论指导和新的思路。

"Lipotoxicity" is an important pathological basis of type 2 diabetic cardiomyopathy, which leads to cardiomyocyte loss, cardiac fibrosis and cardiac dysfunction. The underlying specific pathogenesis is not well elucidated. The present research team found that Mammalian Sterile20-like Kinase1 (Mst1) plays a key role in "glycotoxicity" and type 1 diabetic cardiomyopathy. However, whether Mst1 mediates myocardial injury induced by "lipotoxicity" in type 2 diabetes in not clear. Our study found that in type 2 diabetes, "lipotoxicity" may promote the direct binding of transcription factor FoxO3 with Mst1 gene promoter, thus up-regulate the expression of Mst1 and induce subsequent myocardial injury. However, how does Mst1 mediate diastolic and systolic dysfunction in type 2 diabetic cardiomyopathy? The underlying mechanisms need to be elucidated. Our research group intends to reveal the specific molecular mechanism of "lipotoxicity" regulating FoxO3 / Mst1 signaling pathway and aggravating type 2 diabetic cardiomyopathy from the aspects of gene transcription, protein expression and post-translation modification of protein. The successful implementation of this project may clarify the key molecular mechanism of the occurrence and development of type 2 diabetic cardiomyopathy, and provide theoretical guidance and new ideas for reducing the cardiac mortality of such patients.