几丁质酶3样蛋白1（CHI3L1）调控巨噬细胞极化及其影响心肌纤维化与老年心功能的机制研究

The mechanism of enhanced cardiac fibrosis that leading to ventricular remodeling and decreased cardiac function in aged hearts remains obscure. Previous studies have demonstrated that CHI3L1 induced the secretion of pro-fibrotic factors-TGF-β1 and amphiregulin (AR) after polarization of M2 macrophage. Recently studies found that the expression of TNF-α and CHI3L1 in myocardium of aged mice increased significantly compared with that of young mice. However, the relationship between the two and the involved mechanism of cardiac fibrosis have not been studied so far.. In this study, we will further investigate: (A) the molecular mechanism of expression of CHI3L1 regulated via TNF-α in cardiomyocytes, including the receptors and signal molecules of cardiomyocytes activation; (B) the molecular mechanism of CHI3L1 inducing M2 polarization and functional secretion of macrophage, namely, the receptors, signal molecules and upregulation of functional molecules; (C) the effect and mechanism of CHIL31 on cardiac macrophage infiltration, change in polarity and cardiac fibrosis.. It is hoped that seeking the pathogenesis of senile cardiac fibrosis starting from CHIL31 would improve the understanding of improvement of cardiac dysfunction in senescence.

已知老年心肌纤维化加剧，导致心室重构，心功能降低，但机制仍不明确。前期研究表明，CHI3L1诱导巨噬细胞M2极化后分泌促纤维化因子TGF-β1和双调蛋白（AR）。近期发现，老年鼠心肌组织中TNF-α和CHI3L1表达水平较青年鼠显著上升，但两者的关系以及与心肌纤维化发生的关系及确切机制有待深入研究。.本项目拟探讨：①TNF-α调控心肌细胞CHI3L1表达的分子机制（通过何种受体、信号分子活化心肌细胞？）；②CHI3L1诱导巨噬细胞M2极化及其功能分子分泌的机制研究（通过何种受体、信号分子活化巨噬细胞？上调何种功能分子：TGF-β1、AR及细胞外基质等？）；③CHIL31对心脏巨噬细胞浸润水平、极性改变及心肌纤维化的作用及机制（采用敲基因老年鼠和转基因青年鼠模型）。旨在：CHIL31为切入点，探讨老年心肌纤维化的发病机制，为临床防止老年人心功能降低提供新思路。

老年心肌纤维化是导致恶性心室重构和心功能恶化的重要因素。巨噬细胞在心肌纤维化中发挥重要作用。但老年心脏中浸润的巨噬细胞是如何诱导老年心肌纤维化的发生尚未完全阐明。本研究发现了：1）CpG岛去甲基化导致老年鼠心肌细胞高表达CHI3L1；2）CHI3L1通过IL13Rα2/β-catenin/STAT6通路，促进心脏中浸润的巨噬细胞向M2极化；3）CHI3L1通过诱导巨噬细胞M2极化促进心脏成纤维细胞增殖、迁移及活化；4）体内敲除CHI3L1改善老年鼠心功能，减少老年鼠心肌间质损伤和降低老年鼠心肌纤维化水平。通过本研究我们进一步揭示了CHI3L1及巨噬细胞在老年心肌纤维化中的作用及机制，为防治老年心肌纤维化和缓解老年心衰的发生提供新的思路。