OPOSSUM MODEL FOR THE HIGH & LOW RESPONSES TO DIET

高级负鼠模型

• 批准号: 6620193
• 负责人: RAMPRATAP S KUSHWAHA
• 金额: $ 36.77万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620193
• 关键词: HMG coA reductases; apolipoprotein B; atherosclerosis; blood lipoprotein biosynthesis; blood lipoprotein metabolism; dietary lipid; disease /disorder model; enzyme inhibitors; gene expression; gene mutation; genetic models; genetic polymorphism; genotype; high density lipoproteins; hydroxycholesterols; hyperlipidemia; linkage mapping; low density lipoprotein; messenger RNA; model design /development; nutrition related tag; opossums; polymerase chain reaction; single strand conformation polymorphism; very low density lipoprotein

DESCRIPTION (provided by applicant): The goal of these proposed studies is to develop the laboratory opossum (Monodelphis domestica) as an animal model for investigating metabolic and molecular mechanisms of high and low responses to dietary lipids. Partially inbred strains of opossums exhibit individual differences in very low (VLDL) and low (LDL) density lipoprotein cholesterol concentrations in response to a high cholesterol and high fat (HCHF) diet. These differences are under strong genetic control and a major gene explains 80% of the variability. Thus, the laboratory opossum may be a unique model for investigating the metabolic and genetic basis of lipemic response to diet. An important question that is proposed to answer is whether the major gene is responsive to dietary cholesterol or dietary fat or a combination of both. Based on pervious work, it is hypothesized that the difference in LDL cholesterol concentrations is due to strain differences in LDL apoB production. To test this hypothesis, LDL apoB synthesis will be conducted, cholesterol absorption and bile acid composition in high and low responding opossums on the chow and HCHF diets will be measured. Dietary cholesterol changes the expression and activity of a number of hepatic genes, and a mutation in any of these genes may affect the handling of excess dietary cholesterol by the liver. Therefore, the expression of a major hepatic and extrahepatic cholesterol responsive genes between high and low responding opossums will be measured and compared. If the activity or the expression of a major cholesterol responsive gene is associated with the lipemic responsiveness, a search for a polymorphism by single-strand conformation polymorphism analysis will be done. If a polymorphism in the gene is also associated with the response, selectively bred animals will be genotyped and these data used for linkage analysis to determine if this is the major gene detected by genetic analysis. It is possible that this gene may also be a major determinant of die-induced hyperlipidemia in humans. However, even if this is not the case, these studies are likely to lead to new strategies in the management of diet-induced hyperlipidemia and atherosclerosis in humans.

描述（由申请人提供）：这些拟议研究的目的是 开发实验室负鼠（单层家族）作为动物模型 研究高反应的代谢和分子机制 饮食脂质。 负鼠的部分近交菌株表现出个体 非常低（VLDL）和低（LDL）密度脂蛋白胆固醇的差异 响应高胆固醇和高脂肪（HCHF）饮食的浓度。 这些差异在强大的遗传控制之下，主要基因解释了 80％的变异性。 因此，实验室负鼠可能是一个独特的模型 用于研究脂肪反应对饮食的代谢和遗传基础。 提议回答的一个重要问题是主要基因是否是 对饮食胆固醇或饮食脂肪的反应或两者的组合。 基于详尽的工作，假设LDL的差异 胆固醇浓度是由于LDL APOB的应变差异引起的 生产。 为了检验该假设，将进行LDL APOB合成， 高和低反应的胆固醇吸收和胆汁酸组成 将测量Chow和HCHF饮食上的负鼠。 饮食胆固醇 改变许多肝基因的表达和活性，A 这些基因中的任何一个突变都可能影响处理过多的饮食 肝脏胆固醇。 因此，主要肝和 高反应和低反应之间的肝外胆固醇反应性基因 负鼠将进行测量和比较。 如果活动或表达 一个主要的胆固醇反应基因与脂肪有关 响应能力，通过单链构象寻找多态性 将进行多态性分析。 如果基因中的多态性也是 与反应相关，有选择性的育种动物将是基因分型的，并且 这些用于链接分析的数据，以确定这是否是主要基因 通过遗传分析检测。 这个基因也可能是 人类死亡引起的高脂血症的主要决定因素。 但是，即使 事实并非如此，这些研究可能会导致新的策略 人类饮食引起的高脂血症和动脉粥样硬化的管理。