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: 7385075
• 负责人: NOBUYO MAEDA
• 金额: $ 34.44万
• 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/7385075
• 关键词: 3' Untranslated Regions; Adipose tissue; Adrenal Cortex; Adult; Affect; African American; Alleles; Angiotensin Type 1a Receptor; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atherosclerosis; Blood Pressure; Body fat; Breeding; CYP3A4 gene; CYP3A5 gene; Calcium Channel Blockers; Candidate Disease Gene; Cardiovascular system; Central obesity; Classification; Code; Complex; Complications of Diabetes Mellitus; Condition; Corticosterone; Cytochrome P450; Disease; Dissection; Duct (organ) structure; Elements; End Point; Environment; Enzymes; Essential Genes; Essential Hypertension; Fatty acid glycerol esters; Gene Expression; Gene Targeting; Genes; Genetic Polymorphism; Genomics; Goals; Heart Hypertrophy; Heterozygote; Homologous Gene; Human; Human Genome; Hypertension; Individual; Inherited; Insulin Resistance; Kidney; Measures; Metabolic syndrome; Methods; Modeling; Modification; Molecular; Morbidity - disease rate; Mouse Strains; Mus; Obesity; Outcome; Paper; Partner in relationship; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Play; Polymerase Chain Reaction; Population; Procedures; Proteins; RNA Splicing; Receptor, Angiotensin, Type 1; Relative (related person); Renin-Angiotensin System; Reporting; Research Personnel; Risk; Role; Single Nucleotide Polymorphism; Site-Directed Mutagenesis; Smooth Muscle Myocytes; Social Welfare; Sodium; System; Testing; Therapeutic; Tissues; Validation; Variant; Work; arachidonate; base; blood pressure regulation; cardiovascular risk factor; cytochrome P450 3A; defined contribution; improved; in vivo; mortality; novel strategies; programs; receptor; recombinase; steroid hormone; steroid hormone metabolism; tool; trend

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(申请人提供)：我们研究的长期目标是确定人类基因组的某些多态变异是否在常见疾病中起致病作用，如高血压、胰岛素抵抗、腹型肥胖和动脉粥样硬化，这些都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，人类基因组中影响基因产物表达水平的常见变异在确定风险方面发挥着重要作用。虽然个体变异的影响可能很小，但当它们普遍存在时，它们对整个人口的影响可能会很大。为了模拟这些形式的数量变化，我们建议开发一种新的系统程序，使小鼠的基因表达水平能够随意改变。这一过程依赖于对基因3‘非翻译区(UTR)序列的靶向修饰，以产生在全身具有低(或高)基因表达但能够增加(或降低)特定组织表达水平的小鼠。当小鼠与携带Cre重组酶基因的动物交配时，在全身或以特定组织的方式，表达将从“低”变为“高”，或反之亦然。我们建议将这一新方法应用于血管紧张素II 1型受体(Agtr1a)和细胞色素P450 3a11(Cyp3a11)的编码基因，这两个基因分别是一个公认的高血压基因和一个新的候选基因。我们将使用血压和体脂质量以及由此产生的小鼠的分布作为两个主要的定量终点。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数量变异是否会对复杂疾病产生因果影响，这是关系到人类福祉的一个非常重要的问题。我们培育的“低-高”小鼠品系应该有助于区分基因表达的局部和系统影响，并允许进一步剖析潜在的分子机制。