MicroRNA-9及其宿主基因FSTL1协同调控心肌细胞持久生存的机制研究

Cardiomyocyte cell death is a critical component underlying the onset and development of myocardial diseases. Understanding sustained survival of cardiomyocytes is critical for developing new therapies for myocardial diseases. We and others have identified follistatin-like 1 (FSTL1) as a key regulator against cardiomyocyte apoptosis under various pathological conditions. However, the mechanisms have not been fully understood. Recently, we observed an increase of FSTL1 expression in lipopolysaccharide/doxorubicin-induced cardiomyopathy in mice and treatment of FSTL1 prevents cytotoxicity and mitochondrial dysfunction in above disease models. Moreover, we also illustrated that FSTL1 is directly regulated by miR-9. Inhibition of miR-9 activity is linked to enhanced expression of FSTL1 and sustained survival of cardiomyocytes. These results have led to the hypothesis of this proposal that, miR-9/FSTL1 axis controls the mitochondrial pathway of apoptosis in cardiomyocytes. Completion of this project will provide a novel clue for therapeutic intervention aimed at enhancing cardiomyocyte survival in a variety of disease states such as septic and doxorubicin-induced cardiomyopathy.

心肌细胞丢失对心脏疾病发生发展起决定作用。如何保护心肌细胞持久生存是迫切需要解决的医学难题。申请者及同行已经证实滤泡素抑制素样蛋白1（Follistatin-like 1，FSTL1）参与病理状态下心肌细胞凋亡抵抗过程，但具体机制尚不清楚。最近我们发现脓毒症/阿霉素心肌病小鼠心脏FSTL1表达显著上升，补充外源性FSTL1可以减轻细胞凋亡和线粒体损伤。另外，我们又在FSTL1 3’UTR区找到了miR-9的保守结合位点，并证实miR-9直接靶向FSTL1参与细胞存活稳态维持。因此，我们提出miR-9/FSTL1轴可能是心肌细胞调控线粒体凋亡途径维持持久生存的重要节点，并将从整体动物、心肌细胞和线粒体亚细胞水平验证以上假说。最后，本课题将研制XPack-FSTL1外泌体，并评估其潜在临床应用价值。本项目将深化我们对心肌损伤生物学本质的认识，并为脓毒症/阿霉素心肌病的治疗提供新思路。

心肌细胞丢失对心脏疾病发生发展起决定作用，如何保护心肌细胞持久生存是迫切需要解决的医学难题。已有研究表明滤泡素抑制素样蛋白1（Follistatin-like 1，FSTL1）是维持心脏稳态的重要内源性活性因子。我们发现miR-9负向调控FSTL1表达，并且miR-9通过直接靶向FSTL1参与心肌细胞存活稳态失衡与病理重塑过程，由此我们提出miR-9/FSTL1轴是心肌细胞抵抗凋亡、持久生存的重要节点。机制层面，我们证实miR-9/FSTL1通过Akt信号辅助心肌细胞抵抗凋亡和线粒体损伤，并且BMP通路不参与此过程。最后，我们提出以高表达FSTL1的间充质干细胞（mesenchymal stromal/stem cells, MSCs）治疗心脏疾病的全新治疗模式。