糖尿病心肌病（DCM）是糖尿病患者死亡的主要原因，其重要特征为心肌纤维化。申请人前期发表文章报道Nrf2激活可有效抑制DCM心肌纤维化，但上游机制尚未阐明。我们通过基因芯片筛选发现高糖培养的成人心肌成纤维细胞中长链非编码RNA（lncRNA) NORAD高表达，且 lncRNA NORAD可下调Nrf2及下游HO-1表达，促进高糖诱导的心肌纤维化。进一步预实验提示：高糖条件下lncRNA NORAD可能将RNA结合蛋白FUS和去乙酰化酶HDAC6锚定于Nrf2基因启动子区域，并通过HDAC6下调Nrf2表达。据此本项目提出“lncRNA NORAD通过FUS/HDAC6复合体抑制Nrf2/HO-1通路从而促进DCM心肌纤维化”的假说，运用ChIRP、RIP、ChIP等手段，从表观调控角度揭示lncRNA NORAD参与DCM心肌纤维化的发病机制，为DCM心肌纤维化的防治提供了新思路。

Diabetic cardiomyopathy (DCM) is one of the leading causes of death in diabetic patients, characterized by myocardial fibrosis leading to cardiac dysfunction. Our previous study has revealed that Nrf2 protects cardiomyocytes from diabetic myocardial fibrosis. However, the underlying upstream mechanism is still unclear. Results of the microassay of long non-coding RNA (lncRNA) showed that lncRNA NORAD was significantly up-regulated in adult human cardiac fibroblasts (aHCFs) treated with high glucose compared with that in normal aHCFs. Moreover, lncRNA NORAD promoted diabetic myocardial fibrosis through reducing expression of Nrf2 and its downstream gene HO-1. Further study revealed that lncRNA NORAD bound the Nrf2 promoter and recruited FUS and HDAC6 to reduce the transcript activity of Nrf2 via decreasing the acetylation of core histone under high glucose condition. In light of these, we hereby proposed a mechanistic hypothesis that lncRNA NORAD cooperated with the FUS/HDAC6 complex promotes diabetic myocardial fibrosis through suppressing the Nrf2/HO-1 pathway. The primary objective of this study is to demonstrate the epigenetic mechanism by which lncRNA NORAD regulates the progression of diabetic myocardial fibrosis via several molecular biology methods including ChIRP, RIP and ChIP, consequently offering new insights and identifying new intervention targets for the prevention and treatment of diabetic myocardial fibrosis.