脂肪细胞源exosomes调控PTPN2可变剪接介导的T细胞极化在糖尿病性心肌病中的作用和机制研究

心肌间质纤维化是糖尿病性心肌病（DCM）的主要病理改变，既往多归因于遗传和环境因素，而免疫紊乱在DCM中的研究相对不足。本项目在深入分析DCM研究动态的基础上，认为免疫炎症反应是启动和促进DCM心肌间质纤维化的关键环节。结合前期工作，我们提出糖尿病状态下脂肪细胞源exosomes（ADEs）介导的PTPN2可变剪接/STAT3信号途径是调控糖尿病脂肪代谢性炎症、T细胞极化及心肌间质纤维化核心环节的假说。本项目拟从细胞、动物和临床水平，利用基因工程、质谱分析、分子生物学、细胞生物学及超声心动图等技术，探讨PTPN2可变剪接调控T细胞极化在DCM心肌间质纤维化中的作用，验证ADEs作为调控PTPN2可变剪接的关键因素，是抑制T细胞向促炎/纤维化表型极化、减轻心肌间质纤维化的有效靶点。本课题将打破系统器官之间的作用壁垒，深入阐明DCM的免疫分子调控机制，为精准免疫治疗提供新的理论依据和有效手段。

Myocardial interstitial fibrosis is the main pathological change of diabetic cardiomyopathy (DCM). In the past decades, it was mainly attributed to genetic and environmental factors, while the research on immune disorder in DCM is relatively insufficient. Based on the in-depth analysis of research trends of DCM, it is considered that immune inflammatory response is the key link to initiating and promoting myocardial interstitial fibrosis in DCM. With our previous work, we propose that the PTPN2 alternative splicing/STAT3 signaling pathway mediated by adipocyte-derived exosomes (ADEs) in diabetes might be the core link to regulating adipose metabolic inflammation, T cell polarization and myocardial interstitial fibrosis. Our project intends to explore the role of PTPN2 alternative splicing in regulating T cell polarization and the corresponding effects on myocardial interstitial fibrosis in DCM at cellular, animal and clinical levels, relying on different approaches such as genetic engineering, mass spectrometry, molecular biology, cell biology and echocardiography. It will be verified that ADEs, as an essential factor to regulate PTPN2 alternative splicing, could be an effective target of inhibiting T cells to be polarized to pro-inflammatory/fibrotic phenotype and finally reducing myocardial interstitial fibrosis. This project will break down the barriers among organs of the system, deeply clarify the immune molecular regulation mechanism of DCM, and provide a new theoretical basis aiming at effective means for precise immunotherapy.