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NADPH oxidases in ischemic stroke: cellular sources and pharmacological translation

缺血性中风中的 NADPH 氧化酶：细胞来源和药理学转化

基本信息

批准号：
167057491
负责人：
Professor Dr. Christoph Kleinschnitz
金额：
--
依托单位：
Klinik für Neurologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2010
资助国家：
德国
起止时间：
2009-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/167057491?language=en
关键词：
NADPH oxidases ischemic stroke cellular

项目摘要

Despite tremendous research efforts, recombinant tissue plasminogen activator (rt- PA) is still the only approved compound for the treatment of acute ischemic stroke which represents the second leading cause of death worldwide. Reactive oxygen species (ROS) and oxidative stress are critically involved in the pathophysiology of stroke but their precise role is still unknown. One attractive candidate source for oxidative stress are NADPH oxidases, the only known enzyme family that has ROS as their sole enzymatic product. NADPH oxidases are oligomeric protein complexes, with the NOX subunit catalysing the entire reaction. In rodents 4 NOX genes exist, and in the rodent brain NOX are mainly expressed in neurons and the vasculature with NOX4 being the most abundant isoform. The aim of this project is to elucidate the role of NOX4 in the pathophysiology of ischemic stroke using genetically defined animal models. Transient and permanent cerebral ischemia will be applied to constitutive and tissue specific NOX4 knockout mice. The infarct dynamics will be determined by routine 1.5 T magnetic resonance imaging (MRI) and histology. The penumbra will be quantitatively assessed by using multimodal ultra-high field MRI (17.6 T) including diffusion- (DWI) and perfusion (PWI)-weighted sequences. Furthermore, we can image free radical formation ex vivo and in vivo using conventional techniques (dihydroethidium [DHE] and nitrotyrosine staining) as well as electron paramagnetic resonance imaging (EPRI) through cooperation with Bruker BioSpin GmbH, Karlsruhe, Germany and Prof. Dr. Harald Schmidt, Monash University, Melbourne, Australia. For translating our pathophysiological findings into therapeutic applications, the only specific NOX inhibitor (VAS2870) is available.

尽管进行了大量的研究工作，但重组组织纤溶酶原激活剂（rt-PA）仍然是唯一被批准用于治疗急性缺血性中风的化合物，急性缺血性中风代表了全球第二大死亡原因。活性氧（ROS）和氧化应激在卒中的病理生理学中起着重要作用，但其确切作用仍不清楚。氧化应激的一个有吸引力的候选来源是NADPH氧化酶，这是唯一已知的具有ROS作为其唯一酶产物的酶家族。NADPH氧化酶是寡聚蛋白复合物，其中NOX亚基催化整个反应。在啮齿动物中存在4种NOX基因，并且在啮齿动物脑中NOX主要在神经元和血管中表达，NOX 4是最丰富的同种型。该项目的目的是阐明NOX 4在缺血性中风的病理生理学中的作用，使用遗传定义的动物模型。短暂性和永久性脑缺血将应用于组成型和组织特异性N 0X 4敲除小鼠。将通过常规1.5 T磁共振成像（MRI）和组织学确定梗死动力学。将使用多模式超高场MRI（17.6 T）（包括弥散（DWI）和灌注（PWI）加权序列）定量评估半暗带。此外，通过与Bruker BioSpin GmbH（位于德国卡尔斯鲁厄）和Harald施密特教授（位于澳大利亚墨尔本莫纳什大学）合作，我们可以使用常规技术（二氢乙锭[DHE]和硝基酪氨酸染色）以及电子顺磁共振成像（EPRI）对自由基形成进行离体和体内成像。为了将我们的病理生理学发现转化为治疗应用，唯一的特异性NOX抑制剂（VAS 2870）可用。