细胞外尼克酰胺磷酸核糖转移酶调节脑缺血后神经血管单元急性损伤的作用与机制的研究

Nicotinamide phosphoribosyltransferase is an enzyme that catalyze the synthesis of nicotinamide adenine dinucleotide (NAD), which protects cells by synthesize NAD. However, we found that extracellular NAMPT (eNAMPT) aggravated ischemic-induced neuronal injury via a non-enzymatic effect. Evidences have showed that this effect of eNAMPT may mediated by regulating the dynamic structure and function of neurovascular unit. Thus, we set out this project to explore the underlined mechanisms of eNAMPT on cerebral ischemia. We plan to use in vivo and in vitro ischemic model, and explore: (1) whether and how eNAMPT affects the injury of neurovascular unit ? eNAMPT may affect the neuronal injury, neuronal function and the blood-brain barrier; (2) whether and how eNAMPT affects the cell members of neurovascular unit ? eNAMPT may induces the injury, activation, the expression and release of active substances (cytokine, ROS, MMPs) of microglia, astrocyte, neuron and vascular endgothelial cell; (3) whether and how eNAMPT affects the dynamic interactions between the cell member of neurovascular unit; (4) we will produce the neutralizing antibody of NAMPT and evaluate whether the antibody has potential therapeutic effects against ischemic stroke. The successful implementation of this project will deepen our understanding about the pathological processes after ischemic stroke, promote our understanding about non-enzymatic activity of NAMPT. Furthermore, this project may yield the discovery of a novel multi-functional therapeutic target and lead compounds against the treatment of ischemic stroke.

尼克酰胺磷酸核糖转移酶（NAMPT）的经典作用是催化合成NAD，而对细胞产生保护作用，但我们发现胞外NAMPT能加重脑缺血损伤，该作用与其合成NAD无关。有证据表明，胞外NAMPT的作用可能通过调节神经血管单元的结构和功能实现。为揭示胞外NAMPT加重脑缺血损伤的机制，本项目拟在整体和细胞脑缺血模型，通过观察胞外NAMPT：① 对神经血管单元损伤的作用和机制，包括神经损伤、神经功能、血脑屏障；②对神经血管单元各组成细胞的作用及机制（包括损伤、激活、活性分子表达释放）；③对细胞间相互作用的调节作用和机制；④制备NAMPT中和抗体，观察其对脑缺血损伤是否有保护作用。分析胞外NAMPT如何通过调节神经血管单元的结构、功能和细胞间相互作用，加重脑缺血损伤。本项目研究将促进对NAMPT非酶作用及脑缺血病理过程的认识，为脑缺血治疗提供新的靶点。