Increasing sensitivity to enviromental stress by humanizing NOS2 in mouse

通过人源化小鼠 NOS2 提高对环境压力的敏感性

• 批准号: 8072965
• 负责人: CAROL Anne COLTON
• 金额: $ 1.03万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-24 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072965
• 关键词: Accounting; Acute Disease; Affect; Age; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Antioxidants; Biological Models; Brain; Cardiovascular system; Characteristics; Chronic; Chronic Disease; Degenerative Disorder; Development; Diet; Disease; Disease Progression; Dyslipidemias; Environment; Environmental Exposure; Environmental Risk Factor; Equilibrium; Etiology; Fatty acid glycerol esters; Functional disorder; Gene Mutation; Genes; Genetic; Goals; Human; Immune response; Immunosuppression; Individual; Insulin Resistance; Lead; Lesion; Metabolic stress; Metabolic syndrome; Modeling; Mouse Strains; Mus; Mutate; Mutation; NOS2A gene; Nerve Degeneration; Neurodegenerative Disorders; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Oxidative Stress; Pathology; Play; Preparation; Process; Research; Risk Factors; Rodent; Role; Series; Stress; Symptoms; Time; Tissues; Transgenic Mice; Translating; Translational Research; Water Stress; base; environmental stressor; familial Alzheimer disease; feeding; human disease; innate immune function; mouse model; novel; nutrition; public health relevance; research study; sugar; tool

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.

描述（由申请人提供）：阿尔茨海默病 (AD) 等慢性脑部疾病影响着美国约 500 万人。虽然在识别引发神经退行性疾病过程的特定突变基因方面取得了进展，但当无法识别特定基因或因子时，我们对许多神经退行性疾病病因学的信息有限。重要的是，大多数神经退行性疾病小鼠模型都使用突变基因，尽管人类突变在受影响个体中所占的比例非常低。大脑慢性疾病的特点是先天免疫反应，该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，我们构建了一种新型“人源化”小鼠模型，该模型表达人类 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前体蛋白 (APPSwDI/huNOS2/mNOS2-/-) 的 APP 转基因小鼠杂交。我们发现，通过将小鼠体内的 NO 水平降低至更典型的人类水平，我们现在观察到了类似 AD 疾病进展的特征，而这在其他 AD 小鼠模型中是没有发现的。小鼠和人类的情况也因环境因素的存在而有所不同，例如压力和营养过剩，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疾病的发展。 使用我们新型的“人性化”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压力源中。这种“人性化”的环境结合了高脂肪/高糖饮食和冷水压力。 HuNOS2/mNOS2-/-小鼠的使用将使我们能够首次在小鼠模型中证明，在缺乏已知可在人类中产生 AD 的突变人类基因的情况下，环境应激可以诱导完全的 AD 样病理学。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改变。 公共健康相关性：拟议的研究将在新型“人源化”小鼠模型中研究环境因素对慢性神经退行性疾病发病和进展的作用。