Creating a mouse model for neurodegenerative disease by "humanizing" NOS2

描述（由申请人提供）：我们的目标是产生与阿尔茨海默病非常相似的小鼠模型。在我们的第一次尝试中，我们已经开发了两种AD小鼠模型，其从A β产生和淀粉样蛋白沉积进展到AD相关表位处的过度磷酸化的天然小鼠tau，tau重新分布到神经元的体树突区域，聚集的tau，显著的神经元损失，稳健的行为变化和神经血管单位参与（参见初步数据）。这些新模型在小鼠一氧化氮合酶2（NOS2）敲除背景上表达人APP突变。NOS2及其基因产物iNOS通过产生一氧化氮（NO）在神经炎症中发挥重要作用，一氧化氮是脑中的关键信号和氧化还原因子。神经炎症是慢性神经退行性疾病的不变特征。重要的是，与啮齿动物相比，NOS 2基因存在关键差异，这些差异影响人类免疫反应期间NO的产生。在突变的人APP存在下，小鼠中NOS2基因的遗传缺失为AD的病理学提供了重要的见解。然而，我们假设其中包括启动子的人NOS2基因替换小鼠NOS2基因并且还表达突变的人APP的靶向替换小鼠将是AD的定义模型。这个R21/R33项目建议在R21阶段开发这样的小鼠，然后对所产生的病理进行表型分析，并在R33阶段测试淀粉样蛋白级联假说。公共卫生相关性：我们的目标是产生一种与阿尔茨海默病非常相似的小鼠模型。我们假设，具有更像人类的免疫反应（其中NOS2小鼠基因被人类NOS2基因取代）并表达人类突变淀粉样蛋白前体的小鼠将促进疾病的进展，而不仅仅是淀粉样蛋白沉积。这将提供一个现实的AD小鼠模型，用于研究和开发合理有效的治疗AD的药物。

DESCRIPTION (provided by applicant): Our goal is to generate a mouse model that closely resembles Alzheimer's Disease. In our first attempt we have developed two mouse models of AD that progress from A¿ production and amyloid deposition to hyperphosphorylated native mouse tau at AD-associated epitopes, redistribution of tau to somatodendritic regions of neurons, aggregated tau, significant neuronal loss, robust behavioral changes and neurovascular unit involvement (see preliminary data). These new models express human APP mutations on a mouse nitric oxide synthase 2 (NOS2) knockout background. NOS2 and its gene product, iNOS play an important role in neuroinflammation by generating nitric oxide (NO), a critical signaling and redox factor in the brain. Neuroinflammation is an invariant feature of chronic neurodegenerative disease. Importantly, critical differences exist in the NOS2 gene that impact the production of NO during an immune response in humans compared to rodent. Genetic deletion of the NOS2 gene in mouse in the presence of mutated human APP has provided important insights into the pathology of AD. However, we hypothesize that a targeted replacement mouse where the human NOS2 gene including the promoter replaces the mouse NOS2 gene and that also expresses mutated human APP will be a defining model for AD. This R21/R33 project proposes to develop such a mouse in the R21 phase and then to phenotype the resulting pathology and test the amyloid cascade hypothesis in the R33 phase. PUBLIC HEALTH RELEVANCE: Our goal is to generate a mouse model that closely resembles Alzheimer's Disease. We hypothesize that a mouse with a more human-like immune response (in which the NOS2 mouse gene is replaced by a human NOS2 gene) and expresses human mutated amyloid precursor will promote progression of the disease beyond amyloid deposition alone. This will provide a realistic mouse model of AD to study and to use in the development of rational and effective therapeutics for AD.