Increasing sensitivity to enviromental stress by humanizing NOS2 in mouse

描述(申请人提供)：阿尔茨海默病(AD)等慢性脑部疾病在美国估计有500万人受到影响。虽然在识别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，但当特定基因或病原体无法识别时，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，尽管人类突变在受影响个体中所占比例非常低。慢性脑部疾病的特点是一种促成疾病过程的先天免疫反应。由于小鼠和人类的先天免疫功能存在本质差异，我们创造了一种新的人源化小鼠模型，它表达人的NOS2基因而不是小鼠的NOS2基因(HuNOS2/mNOS2-/-)。我们还将这只小鼠与表达突变的人淀粉样前体蛋白(APPSwDI/huNOS2/mNOS2-/-)的APP转基因小鼠进行了杂交。我们表明，通过将小鼠体内的NO水平降低到更典型的人类水平，我们现在观察到了类似AD的疾病进展的特征，这些特征在其他AD小鼠模型中没有发现。小鼠和人类的情况也因环境因素的存在而不同，如压力和过度营养，这些因素会引发/加速包括代谢综合征(MS)在内的慢性疾病。我们假设代谢综合征同样会加速神经退行性变的发展。 利用我们的新型“人源化”小鼠，我们建议将小鼠暴露在一种已知会导致小鼠代谢综合征的环境应激源中。这种“人性化”的环境将高脂肪/高糖饮食与冷水压力结合在一起。使用HuNOS2/mNOS2-/-小鼠将使我们能够首次在小鼠模型中证明，在没有已知在人类中产生AD的突变人类基因的情况下，环境应激可以诱导完整的AD样病理。使用APPSwDI/huNOS2/mNOS2-/-将使我们能够确定表达人类疾病基因的小鼠的发病和/或疾病进展是否发生了变化。 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在慢性神经退行性疾病发生和发展中的作用。

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.