肾纤维化的发病机制是当前研究热点。我们课题组研究发现：在单侧输尿管结扎（UUO）的小鼠肾纤维化模型中，间质组织纤维化程度增加,同源盒A5基因（HOXA5）启动子区域的甲基化水平升高，而其编码蛋白HoxA5的表达降低。HoxA5是DNA结合转录因子，在多种疾病和肿瘤中发挥重要作用。但其在肾脏纤维化中的意义尚不明了。为了研究HOXA5基因启动子的高甲基化在肾纤维化中的意义，本项目拟在前期工作基础上，从以下几个方面进行研究：探讨肾纤维化导致HOXA5高甲基化的分子机制；分析HOXA5启动子高甲基化与HoxA5蛋白表达程度、以及与肾纤维化之间的关系；探索在肾纤维化中HoxA5通过调节哪些靶基因的转录而影响肾纤维化的发生和发展。本项目将为肾纤维化的分子机制研究提供新的视野。

Kidney fibrosis is a pathological processs leading to the end stage of CKD. Our preliminary data show that in the Unilateral Ureter Obstruction （UUO）model of mouse renal fibrosis，the DNA methylation increased in the promoter region of HOXA5 gene, which is accompanied by decreased HoxA5 protein expression. HOXA5 is one of the Homeoboxgene encoding the DNA-binding transcription factor that plays many important roles such as regulating gene transcription and cell differentiation. To investigate the role of DNA methylation of HOXA5 in kidney fibrosis, we will first exam the mechanism that kidney fibrosis leads to the hypermethylation of HOXA5. We will also verify whether DNA hypermethylation of HOXA5 promoter results in the silence of HoxA5 and then exam the contribution of HoxA5 to the progression of kidney fibrosis. To further understand the underlying mechanism, we will identify the targeting genes of HoxA5 and analyze their roles in kidney fibrosis.