神经内分泌系统过度激活/持续损害是慢性心衰发生重要原因，但有诸多机制亟待探明。本课题组聚焦神经内分泌因子CgA-CST（Chromogranin A-Catestatin），发现：CgA-CST失衡引起血清CgA/CST水平升高与射血分数降低型心衰（HFrEF）发病、严重程度及预后相关；高水平CgA/CST的HFrEF患者血清中CgA出现糖基化修饰，造成纤溶酶结合障碍且CST生成减弱，而糖基化修饰主要发生于高尔基体中；构建脂质体-聚乙二醇包裹的介孔二氧化硅纳米材料负载CST可增强CST稳定性和生物利用度。后续，本项目将挖掘CgA-CST失衡机制及再平衡手段，包括：1）阐明心衰演进中CgA糖基化修饰机制；2）明确糖基化CgA对心力衰竭的影响；3）探寻增强糖基化CgA与纤溶酶结合力的辅助分子；4）揭示脂质体包载CST在HFrEF中的作用。研究成果将为探寻新型HFrEF治疗方案提供理论依据。

Excessive activation of the neuroendocrine system and then sustained damage to the organs is an important cause of chronic heart failure, still many unknown mechanisms need to be identified. We focused on the neuroendocrine factor CgA-CST (Chromogranin A-Catestatin) in former studies. Firstly, it was found through clinical researches that the level of serum CgA/CST caused by the imbalance of neuroendocrine factor CgA-CST were closely associated with the incidence of heart failure with reduced ejection fraction (HFrEF), as well as the severity and prognosis of the disease. Secondly, glycosylation-modified chromogranin A (Gly-CgA) was identified in HFrEF patients with higher levels of CgA/CST by Western blot and in vitro cardiac microscopy. The plasmin-binding disorder with Gly-CgA causes the reduced degradation ability of CgA to produce a decrease in CST, and the Golgi is an organelle in which glycosylation of CgA is modified. In addition, the assembled liposome-polyethylene glycol-coated mesoporous silica nanoparticle material was successfully to enhance the CST half-life time and bioavailability. On one hand, this project will deeply explore the mechanisms of CgA-CST imbalance including to clarify the modification process of Gly-CgA during the progression of heart failure and the effects of Gly-CgA on the structure and function of failing hearts. On the other hand, acquiring CgA-CST rebalance methods, including to identify auxiliary molecules enhancing the binding ability of Gly-CgA to plasmin and reveal the protective effect of liposome-encapsulated CST in HFrEF, will be studied. The results will help to improve the role of the neuroendocrine system in the development of HFrEF, and provide a theoretical basis for exploring new HFrEF treatment options.