Nrf2在II型糖尿病引起的阿尔茨海默症的发病和治疗中的作用和机制研究

Nuclear factor erythroid 2-related factor 2(Nrf2) is a member of the cap 'n' collar (CNC) subfamily of transcription factors and contains a basic leucine zipper domain. It is found to be ubiquitiously expressed in many tissues, and works as the key regulator against oxidative stress damage in cells and organs, which makes Nrf2 a widely concerned drug target. Recent research has identified that Nrf2 is involved in the pathology of type II diabetes mellitus or Alzheimer’s disease, whereas the mechanism is unknown. This project intends to use the mouse model of type II diabetes and type II diabetes induced Alzheimer's disease mouse model to confirm the role of Nrf2 in the pathologic process of type II diabetes induced Alzheimer's disease through Nrf2-Keap1-ARE pathway and the effects of Nrf2 agonist on cognitive dysfunction in mice models. The aim of this study is to further clarify the pathogenesis of type II diabetes induced Alzheimer's disease and discover new drug targets to provide theoretical basis for the research and development of new drugs.

核因子E2相关因子2(nuclear factor erythroid 2-related factor 2，Nrf2)是一个富含亮氨酸拉链结构的Cap-n-collar(CNC)转录因子家族成员，普遍表达于各种组织中，是细胞和机体对抗氧化应激损伤的关键调控者，已成为广受关注的药物靶点。研究显示，Nrf2与II型糖尿病及阿尔兹海默症的发病均有关系，但具体机制尚不清楚。本项目拟利用II型糖尿病小鼠模型、II型糖尿病-阿尔兹海默症双疾病小鼠模型，确认Nrf2参与II型糖尿病引起的阿尔兹海默症的发病，阐明Nrf2通过调节Nrf2-Keap1-ARE及上下游信号通路参与病理过程，并研究Nrf2激动剂对疾病小鼠认知功能障碍的改善作用。本项目的目标是进一步阐明II型糖尿病引起的阿尔兹海默症的发病机制、发现新的药物靶点，并为研发新型药物提供理论依据。

核因子E2相关因子2(nuclear factor erythroid 2-related factor 2，Nrf2)是一个富含亮氨酸拉链结构的Cap-n-collar(CNC)转录因子家族成员，普遍表达于各种组织中，是细胞和机体对抗氧化应激损伤的关键调控者，已成为广受关注的药物靶点。研究显示，Nrf2与II型糖尿病及阿尔兹海默症的发病均有关系，但具体机制尚不清楚。本项目利用II型糖尿病小鼠模型、阿尔兹海默症小鼠模型、II型糖尿病-阿尔兹海默症双疾病小鼠模型、Nrf2敲除小鼠模型，确认Nrf2参与II型糖尿病引起的阿尔兹海默症的发病，阐明Nrf2通过调节Nrf2-Keap1-ARE及上下游信号通路参与病理过程，研究Nrf2激动剂对疾病小鼠认知功能障碍的改善作用，并且发现小分子Keap1-Nrf2蛋白相互作用抑制剂NXPZ可显著改善小鼠的认知功能障碍。通过研究，本项目进一步阐明了II型糖尿病引起的阿尔兹海默症的发病机制、发现新的药物靶点，并为研发新型药物提供更多理论依据。