Role of oxidative stress for neuro-vascular function

氧化应激对神经血管功能的作用

• 批准号: 522474646
• 负责人: Professor Dr. Nikolaus Plesnila
• 金额: --
• 依托单位: Institut für Schlaganfall- und Demenzforschung (ISD)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/522474646?language=en
• 关键词: Role; oxidative; stress; neuro; vascular

Reactive oxygen species (ROS) play a detrimental role upon reperfusion from cerebral ischemia, the current standard therapy for ischemic stroke. However, the exact vascular and cellular mechanisms of this "reperfusion injury" remain unknown mainly due to the lack of methodology to measure ROS in vivo and the lack of animal models that allow to investigate the controlled temporal and spatial induction of ROS. The current project will use novel chemogenetic technology to measure and induce ROS in a cell and organelle-specific manner in vitro and in vivo. These chemogenetic tools will be used in combination with in vivo 2-photon microscopy, single-cell transcriptomics, and a cell-based drug screening platform to 1) measure ROS in a mouse stroke model in cells of the neurovascular unit (NVU) to identify the cellular source of ROS production during reperfusion from cerebral ischemia, 2) to induce ROS production in the NVU of healthy animals to identify the specific role of ROS for neurovascular function, 3) to identify genes induced by cell-specific ROS production, and 4) to identify drugs which prevent or suppress ROS production. The results of the current project will identify the temporal and cellular profile of ROS production after cerebral ischemia, decipher the underlying gene expression, and identify effective antioxidative compounds thereby defining novel molecular and cellular targets and potential drugs for the treatment of stroke patients.

活性氧（ROS）在脑缺血再灌注时发挥有害作用，是目前缺血性卒中的标准治疗方法。然而，这种“再灌注损伤”的确切血管和细胞机制仍然未知，主要是由于缺乏体内测量ROS的方法，以及缺乏允许研究ROS的受控时间和空间诱导的动物模型。目前的项目将使用新的化学遗传学技术来测量和诱导活性氧在细胞和细胞器特异性的方式在体外和体内。这些化学遗传学工具将与体内双光子显微镜、单细胞转录组学和基于细胞的药物筛选平台组合使用，以1）测量小鼠中风模型中神经血管单位（NVU）细胞中的ROS，以鉴定脑缺血再灌注期间ROS产生的细胞来源，2）在健康动物的NVU中诱导ROS产生以鉴定ROS对于神经血管功能的特定作用，3）鉴定由细胞特异性ROS产生诱导的基因，和4）鉴定防止或抑制ROS产生的药物。目前项目的结果将确定脑缺血后ROS产生的时间和细胞概况，破译潜在的基因表达，并确定有效的抗氧化化合物，从而确定新的分子和细胞靶点以及治疗中风患者的潜在药物。