OPOSSUM MODEL FOR THE HIGH & LOW RESPONSES TO DIET

高级负鼠模型

• 批准号: 6400033
• 负责人: RAMPRATAP S KUSHWAHA
• 金额: $ 34.52万
• 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/6400033
• 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）：这些拟议研究的目标是 开发实验室负鼠（Monodelphis Domestica）作为动物模型 研究高和低反应的代谢和分子机制 膳食脂质。 负鼠的部分近交系表现出个体特征 极低（VLDL）和低（LDL）密度脂蛋白胆固醇的差异 高胆固醇和高脂肪（HCHF）饮食的浓度。 这些差异受到强大的遗传控制，一个主要基因解释了这些差异 80%的变异性。 因此，实验室负鼠可能是一个独特的模型 用于研究饮食对血脂反应的代谢和遗传基础。 建议回答的一个重要问题是主基因是否是 对膳食胆固醇或膳食脂肪或两者的组合有反应。 根据以往的工作，假设 LDL 的差异 胆固醇浓度是由于 LDL apoB 的菌株差异造成的 生产。 为了检验这一假设，将进行 LDL apoB 合成， 胆固醇吸收和胆汁酸组成的高低反应 将测量负鼠的食物和 HCHF 饮食。 膳食胆固醇 改变许多肝脏基因的表达和活性， 这些基因中任何一个的突变都可能影响过量饮食的处理 胆固醇通过肝脏。 因此，主要肝脏和 高反应和低反应之间的肝外胆固醇反应基因 负鼠将被测量和比较。 如果活动或表达 主要胆固醇反应基因与血脂相关 响应性，通过单链构象寻找多态性 将进行多态性分析。 如果基因也存在多态性 与反应相关，选择性繁殖的动物将被基因分型并 这些数据用于连锁分析以确定这是否是主要基因 通过基因分析检测。 该基因也可能是 人类死亡引起的高脂血症的主要决定因素。 然而，即使 事实并非如此，这些研究可能会带来新的策略 饮食引起的人类高脂血症和动脉粥样硬化的管理。