Nrf2/ARE的新功能- - 促进海马成体神经发生及其BDNF依赖性机制

Nrf2/ARE是机体抵抗内、外界氧化和化学等刺激的重要通路。我们发现，激活Nrf2药物显著促进APP/PS1双转基因或野生小鼠海马成体神经发生，下调Nrf2的表达不仅阻断Nrf2通路激活剂诱导的成体神经发生，而且对APP/PS1双转基因小鼠海马成体神经发生也有一定的抑制。有趣的是，Nrf2通路激活能显著上调海马细胞 BDNF的表达。我们推测Nrf2/ARE可能通过上调BDNF而促进成体海马神经元发生。本课题拟采用Nrf2基因敲除鼠、基因芯片和分子生物学等技术从体内、外研究Nrf2/ARE在调节小鼠成体海马神经元发生中的作用，试图发现Nrf2/ARE调节神经发生的相关基因，进而探讨BDNF等相关因子在其中的作用以及Nrf2/ARE调控这些因子的分子机制。本研究将阐明Nrf2/ARE通路在海马成体神经发生中的新功能及其分子机制，为 "以Nrf2/ARE为靶"调节海马成体神经发生提供科学依据。

Nuelear factor E2-related factor 2/ARE （Nrf2/ARE）signaling pathway is an important redox-sensitive signaling system against oxidative stress or chemicla stress from inside and outside of body. We found that a compound, activating Nrf2/ARE pathway, significantly increased the adult neurogenesis in hippocampus of APP/PS1 transgenic mice. Knock-down of Nrf2 decreased the compound-induced adult neurogenesis and also the original adult neurogenesis in APP/PS1 transgenic mice. It is is interesting that the Nrf2 activators dramatically increaase the brain-derived neurotrophic factor (BDNF) in a mice hippocampal cell line. Basing on these findings, we hypothesize that Nrf2/ARE play a key role in the adult neurogenesis and BDNF paly important role in the process. In current project, we want to investigate the effects of Nrf2/ARE pathway on the adult neurogenesis and the molecular mechanisms in vitro and in vivo using Nrf2-/- mice, gene chip, and molecular biological techniques, and so on. The project is going to eluciate the role(s) and the mechanism(s) of Nrf2/ARE pathway in the adult neurogenesis and to verify that Nrf2/ARE pathway is a novel target for inducing adult neurogensis.