肾间质纤维化是慢性肾脏病不可逆发展的病理机制，故探究如何对抗肾间质纤维化具有重要意义。Nrf2抗肾间质纤维化作用明确，但机制不明。预实验发现Nrf2与纤维化调控因子TEAD1的联系：Nrf2缺失可加重纤维化程度并上调TEAD1表达，沉默TEAD1可纠正Nrf2沉默所致纤维化加重；双荧光素酶报告基因发现Nrf2抑制TEAD1转录；挖掘ChIP测序数据发现去乙酰化复合体NuRD与Nrf2均与TEAD1启动子结合，提示NuRD可能与Nrf2协同作用抑制TEAD1转录。由此提出假设Nrf2通过招募NuRD抑制TEAD1转录从而拮抗肾间质纤维化。本项目拟通过干预和拯救实验阐明Nrf2下调TEAD1起到抗纤维化作用；转录调控实验揭示Nrf2通过招募NuRD下调TEAD1转录的机制；临床验证Nrf2、TEAD1与肾间质纤维化联系。旨在揭示Nrf2与TEAD1转录调控联系以阐明Nrf2抗肾间质纤维化机制。

Renal interstitial fibrosis promotes the progression of chronic kidney disease, thus inhibition of renal interstitial fibrosis has important clinical significance. The anti-fibrosis function of Nrf2 (nuclear factor erythroid-derived 2-like 2) has been verified previously, but the mechanism is still not clear. Our pre-experiment firstly revealed the connection between Nrf2 and pro-fibrosis factor TEAD1 (TEA domain transcription factor 1). Nrf2 knockout upregulated TEAD1 expression accompanied by renal interstitial fibrosis aggravation. Further rescue experiment showed that the aggravation of renal fibrosis induced by Nrf2 knockdown was abolished by TEAD1 knockdown. By re-analyzing reported ChIP-sequence data, Nrf2 was found to be bound with the promotor region of TEAD1 gene. Dual-luciferase reporter gene analysis found TEAD1 transcription can be inhibited by Nrf2. NuRD is deacetylation complex, which can assist transcription factor to inhibit transcription. Re-analyzing reported ChIP-sequence data found that both of NuRD and Nrf2 can bind with the promoter region of TEAD1. Thus, we hypothesized that Nrf2 inhibits TEAD1 transcription by cooperating with NuRD to inhibit renal interstitial fibrosis. In this project we will firstly carry out intervention and rescue experiment to reveal that Nrf2 downregulates TEAD1 to inhibit renal fibrosis. Then we will explore Nrf2 transcriptionally inhibits TEAD1 with the help of NuRD. Finally, we will summarize the association between Nrf2, TEAD1 and fibrosis level in clinical trial. The aim of this project is to explore the transcriptional relationship between Nrf2 and TEAD1 to illustrate the mechanism of Nrf2 induced renal interstitial fibrosis inhibition.