心肌纤维化是多种心脏疾病向心力衰竭发展的重要病理生理过程。目前的干预措施不能有效遏制心肌纤维化的发生发展，阐明心肌纤维化的潜在机制将为临床干预开辟新的道路。转录因子在心肌纤维化过程中发挥关键作用，易洛魁基因家族（Iroquois homeobox factors，IRXs）是一类保守的多功能转录因子，我们前期实验发现，易洛魁同源家族成员IRX2和IRX3（IRX2、3）在压力负荷和缺血损伤诱导的心肌纤维化模型中表达显著上调；IRX2、3基因敲除后，压力负荷诱导的心肌纤维化程度明显加重。但IRX2、3在心肌纤维化中的作用及机制尚不清楚。本项目拟运用成纤维细胞特异性IRX2、3敲除小鼠，构建心肌纤维化模型，阐明IRX2、3在心肌纤维化中的作用，寻找其可能的靶基因及作用机制，并进一步探索IRX2、3调控心脏纤维化的干预机制，为阐明心肌纤维化的机制提供新的理论依据，为心肌纤维化的防治提供新的策略。

Cardiac fibrosis is the key pathophysiologic process of various cardiac diseases which develop to heart failure ultimately. Current interventions can not effectively protect the heart from fibrotic remodeling. Elucidating the potential mechanisms of cardiac fibrosis will provide new approaches for clinical treatment. Transcription factors play important roles in the regulation of cardiac fibrosis. Iroquois homeobox factors (IRXs) is a family of conserved and multifunctional transcription factors. In our preliminary experiment, we found that the expression of the transcriptional factors, IRX2 and IRX3, significantly increased in the heart in pressure overload-induced or myocardial ischemia-induced cardiac fibrosis models. Using IRX2 or IRX3 knockout mice, we found that IRX2 or IRX3 deficiency led to aggravated cardiac fibrosis induced by aortic binding (AB) compared to wild type (WT) mice. However, its role in cardiac fibrosis and the mechanisms remain unclear. We intend to utilize the fibroblast specific knock out mice and cardiac fibroblasts to establish the in vivo and in vitro models of cardiac fibrosis, and to clarify the role of IRX2 and IRX3 in cardiac fibrosis, and more importantly, to identify the direct target genes and explore the signal pathways upstream of IRX2 and IRX3 in cardiac fibrosis furtherly. Our findings presented in this proposal may enhance the current understanding of the mechanism in cardiac fibrosis, and may provide new strategies for the prevention and treatment of cardiac fibrosis.