心肌成纤维细胞转录因子ZFP64的运动敏感性及其调控压力负荷性心肌纤维化重塑的机制研究

心肌纤维化重塑是慢性心力衰竭发展中突出的病理特征，心肌成纤维细胞过度激活是公认的细胞机制，但目前缺乏有效治疗手段。适度规律运动可促进心肌生理生长，加强心肌舒缩功能，抑制成纤维细胞激活。识别心肌成纤维细胞差异响应生理运动与病理应激的关键效应分子及其机制，对控制心肌纤维化重塑潜在着重要意义。我们前期研究通过整合分析转录组测序并实验验证，发现心肌成纤维细胞特异的转录因子ZFP64在运动与压力负荷性重塑的心肌中反向变化。ZFP64表达增加导致心肌成纤维细胞的转分化、呈现纤维化发生的特征，反之则抑制多种病因导致的成纤维细胞激活。成纤维细胞ZFP64基因条件性敲除不影响基础心脏功能与结构。本项目将明确ZFP64在压力负荷性心肌纤维化重塑中的作用；阐明心肌成纤维细胞ZFP64差异响应生理与病理应激，及其调控压力负荷性心肌纤维化重塑的机制；为治疗高血压相关慢性心力衰竭提供新思路与新靶点。

Cardiac fibrosis is the prominent pathological character of chronic heart failure, of which over-activation of cardiac fibroblasts is the cornerstone of cellular mechanism. But there is no available treatment for this. Moderate exercise promotes physiological hypertrophy of myocardium, increases cardiac contractility and inhibits the activation of cardiac fibroblasts. Understanding of the molecular mechanisms of cardiac fibroblasts which differently reacted in physiological exercise and pathological pressure is the key of hunting for new ways to inhibit cardiac fibrosis. By analyzing the RNA-seq datasets, we formerly found ZFP64, a transcription factor, which is specifically expressed in cardiac fibroblasts, is inversely expressed in the cardiac tissues of mice under exercise and pressure overloading. Upregulation of ZFP64 promotes the trans-differentiation and fibrotic formation of cardiac fibroblasts, vice versa. Fibroblast-specific ablation of ZFP64 is with no compromise of basic function and structure of heart. In this project, the role of ZFP64 in pressure overloaded cardiac fibrosis will be addressed; the mechanisms of differences between physiological and pathological activation of ZFP64 in cardiac fibroblast and the genetic network under the regulation of ZFP64 in pressure-overloaded cardiac fibrosis will be clarified. This project will shed a light on the searching for new therapeutic targets of hypertensive chronic heart failure.