Increasing sensitivity to enviromental stress by humanizing NOS2 in mouse

描述（由申请人提供）：脑部慢性疾病，如阿尔茨海默病（AD），在美国影响约500万人。虽然在确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，但当无法确定特定基因或因子时，我们对许多神经退行性疾病的病因学信息有限。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，尽管人类突变占受影响个体的百分比非常低。大脑慢性疾病的特点是先天免疫反应，有助于疾病的进程。由于小鼠和人类的先天免疫功能存在本质差异，我们建立了一种新的“人源化”小鼠模型，表达人类NOS2基因代替小鼠NOS2基因（HuNOS2/mNOS2-/-）。我们还将这只小鼠与表达突变的人类淀粉样蛋白前体蛋白（APPSwDI/huNOS2/mNOS2-/-）的APP转基因小鼠杂交。我们表明，通过将小鼠体内NO水平降低到更典型的人水平，我们现在观察到在其他AD小鼠模型中没有发现的AD样疾病进展的特征。小鼠和人类的情况也因环境因素的存在而不同，如压力和营养过剩，这些环境因素会引发/加速慢性疾病，包括代谢综合征（MS）。我们假设代谢综合征同样会加速神经变性的发展。

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.