Increasing sensitivity to enviromental stress by humanizing NOS2 in mouse

描述（由申请人提供）：在美国，慢性脑疾病如阿尔茨海默病（AD）影响约500万人。虽然在鉴定启动神经退行性疾病过程的特定突变基因方面取得了进展，但当无法鉴定特定基因或试剂时，我们对许多神经退行性疾病的病因学的信息有限。重要的是，大多数神经退行性疾病的小鼠模型使用突变基因，尽管人类突变在受影响的个体中所占比例非常低。大脑的慢性疾病的特征是先天免疫反应，有助于疾病的过程。由于小鼠和人类的先天免疫功能之间存在本质差异，我们已经产生了一种新的“人源化”小鼠模型，其表达人NOS 2基因代替小鼠NOS 2基因（HuNOS 2/mNOS 2-/-）。我们还将该小鼠与表达突变的人淀粉样前体蛋白（APPSwDI/huNOS 2/mNOS 2-/-）的APP转基因小鼠杂交。我们表明，通过将小鼠中的NO水平降低到更典型的人的水平，我们现在观察到在其他AD小鼠模型中未发现的AD样疾病进展的特征。鼠和人的状况也因环境因素的存在而不同，例如引发/加速慢性疾病（包括代谢综合征（MS））的压力和营养过剩。我们假设代谢综合征同样会加速神经变性的发展。 使用我们的新型“人源化”小鼠，我们建议将小鼠暴露于已知会导致小鼠代谢综合征的环境应激源。这种“人性化”的环境将高脂肪/高糖饮食与冷水应激结合在一起。使用HuNOS 2/mNOS 2-/-小鼠将使我们能够在小鼠模型中首次潜在地证明，在已知在人类中产生AD的突变人类基因不存在的情况下，环境应激可以诱导完全AD样病理。使用APPSwDI /huNOS 2/mNOS 2-/-将允许我们确定在表达人类疾病基因的小鼠中是否改变了发病和/或疾病进展。 公共卫生相关性：拟议的研究将在一种新的“人源化”小鼠模型中研究环境因素对慢性神经退行性疾病的发病和进展的作用。

DESCRIPTION (provided by applicant): Chronic diseases of the brain such as Alzheimer's disease (AD) impact an estimated 5 million individuals in the US. While progress has been made in identifying specific mutated genes that initiate a neurodegenerative disease process, we have limited information on etiology of many neurodegenerative diseases when a specific gene or agent cannot be identified. Importantly, most mouse models on neurodegenerative diseases use mutated genes, despite the fact that human mutations account for a very low percentage of affected individuals. Chronic diseases of the brain feature an innate immune response that contributes to the disease process. Since essential differences exist between innate immune function in mice and in humans, we have generated a novel "humanized" mouse model that expresses the human NOS2 gene in place of the mouse NOS2 gene (HuNOS2/mNOS2-/-). We have also crossed this mouse to an APP transgenic mouse that expresses mutated human amyloid precursor protein (APPSwDI/huNOS2/mNOS2-/-). We show that by reducing NO levels in mice to levels more typical of people, we now observe features of AD-like disease progression that are not found in other mouse models of AD. Murine and human conditions also differ by the presence of environmental factors such as stress and over- nutrition that initiate/accelerate chronic diseases including metabolic syndrome (MS). We hypothesize that metabolic syndrome will similarly accelerate the development of neurodegeneration. Using our novel "humanized" mice, we propose to expose mice to an environmental stressor that is known to lead to metabolic syndrome in mice. This "humanized" environment incorporates high fat/high sugar diet with cold-water stress. Use of the HuNOS2/mNOS2-/- mouse will allow us to potentially demonstrate for the first time in a mouse model that full AD-like pathology can be induced by environmental stress in the absence of mutated human genes known to produce AD in humans. Use of the APPSwDI /huNOS2/ mNOS2-/- will allow us to determine if onset and/or disease progression are altered in mice that express human disease genes. PUBLIC HEALTH RELEVANCE: The proposed research will study the action of environmental factors on the onset and progress of chronic neurodegenerative disease in a novel "humanized" mouse model.