尿酸作为缺血性脑卒中的改善治疗手段已进入临床试验阶段，而实验室研究却受限于啮齿类动物与人类尿酸代谢的差异，其作用机制尚不清楚。尿酸氧化酶基因敲除（UOx KO）小鼠拥有“拟人化”嘌呤代谢过程，为研究尿酸神经生物学提供了独特工具。我们前期实验显示，UOx KO小鼠脑内尿酸盐水平升高，Nrf2通路激活。本项目拟制备局灶性脑缺血/再灌UOx KO小鼠模型，研究尿酸对模型小鼠的药效学作用，及其对脑微血管周细胞、脑微循环稳态和Nrf2-Notch通路的影响，明确其作用机制；并应用siRNA技术沉默周细胞内Nrf2、Notch表达，进一步验证尿酸激活Nrf2-Notch通路改善糖氧剥夺/再灌所致周细胞损伤，明确其作用靶点。本项目的实施可能明确尿酸激活Nrf2-Notch通路改善缺血性脑卒中脑微血管周细胞损伤和微循环障碍的新机制，为抗脑缺血药物研发提供新的作用机制和靶点，具有重要科学意义和较高应用价值。

Urate is one of our major endogenous defenses against oxidative stress and accounts for most of the antioxidant capacity in human plasma. Based on the strong pre-clinical evidence of a neuroprotective role for urate in the central nervous system (CNS), recent clinical trials in stroke have begun to examine the feasibility of urate manipulation in a clinical setting with promising results. In rodents, simple supplementation with urate does not lead to appreciable increases in CNS urate levels due to rapid metabolism by urate oxidase. The availability of urate oxidase gene knock out (UOx KO) mice with ‘humanized’ purine biology provides a unique opportunity to test the effects of urate manipulation in mouse model of stroke. As showed by our previous research, UOx KO mice have increased CNS urate levels and activated Nrf2 (Nuclear factor erythroid 2–related factor 2) antioxidant pathway and related expression of anti-oxidant proteins increased. Based on previous experiments, we will be the first one to test the protection effect of urate with UOx KO mice in transient brain ischemia and reperfusion model. We will try to prove urate will decrease the pericytes apoptosis and improve microvasculation dysfunction in vivo and silence Nrf2 and Notch in pericytes using siRNA technology to further test if urate's protection is mediated through the Nrf2-Notch signaling pathway in vitro. We will also treat the mice with the urate to further elevate CNS urate to observe the protection effect of urate. We anticipate that knowledge about urate neurobiology in stroke could expedite translation of urate-targeted approaches to stroke clinical care.