限制型心肌病是以舒张功能异常为特征，表现为限制性充盈障碍的心肌病，目前发病机制尚未明确。蛋白质稳态依赖于蛋白质质量控制系统调节，其失衡与多种心肌病密切相关。ESCRT复合体介导的蛋白分选和降解对于蛋白质稳态至关重要，而ESCRT调节的蛋白质稳态是否与限制型心肌病发生密切相关尚不清楚。Hgs是ESCRT-0亚复合体的重要组分，通过建立心肌细胞特异性Hgs敲除小鼠，我们发现该小鼠可出现典型的限制型心肌病病变，提示Hgs可能在该病发生中发挥重要功能。本研究将继续通过对基因敲除小鼠进行系统的表型分析来明确其在限制型心肌病中的功能。此外，通过对小鼠心脏组织进行蛋白质组学分析和验证，并进一步针对候选分子进行治疗实验来阐明Hgs敲除导致限制型心肌病的分子机制。该研究将为限制型心肌病的发病机制提供新理论，为疾病的治疗提供新策略。建立的基因敲除小鼠也有望成为限制型心肌病药物研发和疗效评价的理想疾病动物模型。

Restrictive cardiomyopathy (RCM) is a cardiomyopathy characterized by restrictive filling disorder resulted from abnormal diastolic function, but the mechanism of RCM is still elusive. Balanced proteostasis depends on proper protein quality control, and its imbalance is related to various cardiomyopathies. Endosomal sorting required for transport (ESCRT)-mediated protein sorting for degradation is crucial for proteostasis. However, whether there exists a direct link between ESCRT-mediated proteostasis and RCM remains unknown. Hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs) is a vital element of ESCRT-0. We generated cardiomyocyte-specific Hgs knockout mice to find that Hgs deletion in cardiomyocytes could result in RCM, suggesting it might play an important role in RCM. In this project, we will further verify the physiological function of Hgs in RCM using Hgs knockout mice. Furthermore, the underlying mechanism of Hgs function in hearts will be elucidated by proteomic analysis of heart tissues, and therapeutic experiments targeting candidate proteins in Hgs knockout mice. This project will develop new theory and therapeutic strategy for RCM. The cardiomyocyte-specific Hgs knockout mice are also expected to be ideal animal models for RCM drug development and efficacy evaluation.