Testing Human Quantitative Genomic Variations in Mice

在小鼠中测试人类基因组数量变异

• 批准号: 6913926
• 负责人: NOBUYO MAEDA
• 金额: $ 36.34万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6913926
• 关键词: angiotensin II; biological models; blood pressure; body composition; cytochrome P450; disease /disorder proneness /risk; gene expression; genetic polymorphism; genetically modified animals; hypertension; laboratory mouse; pathologic process

DESCRIPTION (provided by applicant): The long-term goal of our study is to determine whether certain polymorphic variations in the human genome play causative roles in the common conditions, such as essential hypertension, insulin resistance, abdominal obesity, and atherosclerosis, that are important risk factors for cardiovascular morbidity and mortality. Our working hypothesis is that common variations in the human genome that affect levels of expression of gene products play significant roles in determining risk. While the effect of individual variations may be small, when they are common their impact in the total population can be significant. To model these forms of quantitative variation, we propose to develop a new systematic procedure enabling the levels of gene expression to be altered at will in mice. The procedure depends upon targeted modification of 3'untranslated region (UTR) sequences of genes to generate mice with low (or high) expression of a gene in the whole body yet with the ability to increase (or decrease) the expression level in specific tissues. Expression will be altered from "low" to "high", or vice versa, in whole body or in tissue-specific fashion when mice are mated to an animal carrying a Cre-recombinase gene. We propose here to apply this new procedure to the genes coding for angiotensin II type 1 receptor (Agtr1a) and cytochrome P450 3A11 (Cyp3a11), which are respectively a well-established and a new candidate gene for essential hypertension. We will use blood pressure and body fat mass and distribution of resulting mice as the two primary quantitative endpoints. We expect that our new method will facilitate testing whether other inherited quantitative variants in the human genome have causative effects on complex diseases, a highly important problem in relation to human welfare. The "low-high" strains of mice that we produce should aid in distinguishing between local and systemic effects of gene expression and allow further dissection of the underlying molecular mechanisms.

描述（由申请人提供）：我们研究的长期目标是确定人基因组中某些多态性变化是否在常见条件下起因果作用，例如必需的高血压，胰岛素抵抗，腹部肥胖和动脉粥样硬化，是心血管发病率和死亡率的重要危险因素。我们的工作假设是，影响基因产物表达水平的人类基因组的常见变异在确定风险中起着重要作用。虽然各个变化的影响可能很小，但是当它们很普遍时，它们对总人口的影响可能很大。为了建模这些定量变化形式，我们建议开发一种新的系统过程，以便在小鼠中随意改变基因表达的水平。该过程取决于基因的3'untranslated区域（UTR）序列的靶向修饰，以产生整个体内基因表达低（或高）表达的小鼠，但具有提高（或降低）特定组织中表达水平的能力。当小鼠与携带CRE成年酶基因的动物交配时，表达将从“低”变为“高”，反之亦然。我们在这里建议将此新程序应用于编码血管紧张素II类型1型受体（AGTR1A）和细胞色素P450 3A11（CYP3A11）的基因，它们分别是建立良好的基因和新的候选基因，用于基本高血压。我们将使用血压和体内脂肪质量以及所得小鼠的分布作为两个主要定量终点。我们预计我们的新方法将有助于测试人类基因组中的其他遗传定量变体是否对复杂疾病具有致病作用，这是与人类福利有关的非常重要的问题。我们产生的小鼠的“低高”菌株应有助于区分基因表达的局部和全身效应，并允许对基本分子机制进行进一步解剖。