NAD+/CD38/cADPR信号通路介导脓毒症脑病的分子机制研究

Sepsis associated encephalopathy (SAE) is a common complication of sepsis, with a high incidence and mortality rate, and still without effective treatment. Thus, it becomes a hot research topic recent years. In previous study, we did gene expression profile analysis and identified significantly differential expression of CD38 gene between the brain tissues of SAE and normal rats. Further experiments showed that NAD+, CD38 and cADPR expression significantly up-regulated in the brain tissues of SAE rats in a time-dependent pattern, and cADPR inhibitor treatment significantly alleviated the cerebral injury, which strongly indicated that the NAD+/CD38/cADPR signaling pathway took part in the pathogenesis of SAE. This project plan to use gene recombination technology to activate or inhibit the NAD+/CD38/cADPR signaling pathway and investigate its role in the pathogenesis of SAE; explore the important role of lipid rafts in the activation of this pathway; and study its downstream mechanisms that mediate the cerebral injury. The objective of this project is to clarify the role of NAD+/CD38/cADPR signaling pathway in SAE, therefore provide a new potential target for its treatment.

脓毒症脑病（SAE）是脓毒症的常见并发症，发病率、死亡率高，缺乏有效治疗手段，是近年来研究的热点。我们前期研究通过全基因组表达谱芯片比较分析，发现CD38基因在SAE大鼠与正常大鼠脑组织中存在显著性差异表达，进一步预实验显示SAE大鼠脑组织内NAD+、CD38和cADPR表达均显著增加且具有时间规律性，给予cADPR抑制剂处理后SAE脑损伤明显减轻，强烈提示NAD+/CD38/cADPR信号通路参与介导SAE的发生发展。本项目将从体外和体内两个层面，通过基因重组技术探究NAD+/CD38/cADPR信号通路的激活和抑制对SAE发生发展的影响；探索脂筏介导该通路活化的重要作用；研究该通路介导SAE脑损伤的下游分子机制。最终诠释NAD+/CD38/cADPR信号通路介导SAE的重要作用及其分子机制，研究结果将为SAE的治疗提供新思路和理论依据。

本项目旨在研究NAD+/CD38/cADPR 信号通路在脓毒症脑病（SAE）中的作用及其分子机制。通过动物模型研究，明确了NAD+/CD38/cADPR 信号通路在脓毒症发生发展过程中的动态表达规律，以及抑制NAD+/CD38/cADPR 信号通路减轻海马组织凋亡、氧化应激和超微结构损伤的作用，揭示了NAD+/CD38/cADPR 信号通路介导SAE 脑损伤的分子机制，以及抑制NAD+/CD38/cADPR 信号通路对SAE的保护作用。通过细胞水平研究，揭示了抑制NAD+/CD38/cADPR 信号通路在正常小胶质细胞中促进凋亡和氧化应激，而在炎症情况下反而抑制凋亡和氧化应激的双重作用，在LPS激活的小胶质细胞中抑制该通路能减少LPS诱导的Ca2+内流，减轻细胞凋亡和氧化应激损伤，减少炎性细胞因子的释放，从细胞水平揭示了NAD+/CD38/cADPR 信号通路参与SAE的分子机制及小胶质细胞在神经系统炎症中的重要作用。通过上述研究，最终从动物模型和细胞水平两个层次阐明了NAD+/CD38/cADPR 信号通路在SAE中的作用及其分子机制，为深入理解SAE的发病机制及寻找潜在的治疗靶点提供了理论基础。项目严格按照实验计划进行，充分实现了预期目标，发表SCI论文5篇，培养研究生2名。项目投入18万，支出17.7492万，各项支出基本与预算相符。