心肌纤维化是引发糖尿病性心肌病的最主要原因之一，但机制尚不明确。我们发现环形非编码RNA_005647(circRNA-5647)在糖尿病性小鼠心肌中表达增强，过表达circRNA-5647可促进小鼠心肌成纤维细胞中纤维化相关基因表达，并激活TGFβ1/TGFβR1-PAK1通路，但分子机制不明。RNA pull-down和双荧光素酶报告实验结果证实circRNA-5647与微小RNA miR-221-3p有特异结合作用。推测circRNA-5647通过解除miR-221-3p对靶基因ANGPTL2、TGFβR1和PAK1的抑制作用，激活TGFβ1/TGFβR1-PAK1通路，进而促发心肌纤维化。本项目拟建立circRNA-5647转基因小鼠，从整体-细胞-分子水平，阐明circRNA-5647在糖尿病性心肌纤维化中的作用机制，为进行基于环形非编码RNA的心肌纤维化治疗研究提供科学依据。

Cardiac fibrosis is an important character and cause of the diabetic cardiomyopathy, but the mechanism underlying the diabetic cardiac fibrosis has not been well elucidated. We observed that circular RNA circRNA_005647 was up-regulated in the myocardium of the diabetic mice. Over-expression of circRNA_005647 could significantly enhance the expressions of fibrosis-related genes in mouse myofibroblasts, and activated the TGFβ1/TGFβR1-PAK1 pathway.However, the molecular mechanism underlying the pro-fibrotic effect of circRNA_005647 is still unknown. The results of RNA pull-down and dual luciferase assay revealed the specific interaction between circRNA_005647 and miR-221-3p. We hypothesize that circRNA_005647 sponges miR-221-3p and derepresses the downstream target genes of miR-221-3p, including angiopoietin-like 2(ANGPTL2), TGFβ receptor type I(TGFβR1) and P21 Protein (Cdc42/Rac)-activated kinase 1(PAK1), contributing to the activation of TGFβ1/TGFβR1-PAK1 pathway and cardiac fibrosis. The transgenic circRNA_005647 mice and the wild type control mice, and cardiac fibroblasts derived from the above two kinds of mice will be utilized in the present project. We will demonstrate the mechanism underlying the enhancement of cardiac fibrosis by circRNA_005647 at the whole organism,cellular and molecular level, respectively. The present study is expected to provide scientific evidence and material for developing new therapeutic approaches based on circular RNAs for treatment of diabetic cardiac fibrosis.