MOUSE MODEL FOR HUMAN ATHEROGENIC LIPOPROTEIN PHENOTYPE

人类动脉粥样硬化脂蛋白表型的小鼠模型

• 批准号: 2224781
• 负责人: JUERGEN K. NAGGERT
• 金额: $ 11.6万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-10 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2224781
• 关键词: alleles; atherosclerosis; diabetes mellitus; diabetes mellitus genetics; disease /disorder proneness /risk; gel electrophoresis; gene interaction; gene mutation; genetic markers; genetic polymorphism; laboratory mouse; linkage mapping; low density lipoprotein; nucleic acid sequence; obesity; pathologic process; phenotype; polymerase chain reaction; southern blotting

The phenotype of small dense low density lipoprotein (LDL) appears to play an important role in human atherosclerosis and diabetes. Most human diabetics have small dense LDL particles. Furthermore, a human gene that determines a phenotype of small dense LDL has been found. The allele causing the abnormal phenotype occurs in about 30% of individuals and is associated with upper body obesity, insulin resistance, and a 3-fold increased risk of heart disease. The human gene is named ATHS for atherosclerosis susceptibillty, and we have just mapped this gene to human chromosome 19 at or very near the gene for the LDL receptor. The objective of this grant proposal is to identify and characterize the genetic factor in the mouse responsible for the phenotype of small LDL and to investigate its interaction with other genetic factors controlling atherosclerosis, diabetes and obesity. First we will identify the genetic factor that determines production of small LDL in C57BL/Ks diabetes mice. If we identify the gene, we will sequence it and characterize the mutation causing the small dense LDL. Second, we want to determine the relationship between the small dense LDL genotype and the diabetogenic and atherogenic factors found in the BKs strain. That is, we will determine whether the gene for small dense LDL and the atherogenic or diabetogenic factor are linked or are even the same gene. Should we find, for instance, that small LDL and the atherogenic factor are the same gene, this would show, for the first time directly, that small LDL can lead to atherosclerosis. And third, we plan to determine the relationship between the small dense LDL phenotype and other phenotypic characteristics of the obese-diabetic syndrome in BKs. In particular, we want to answer the question whether the small LDL phenotype is dependent on the diabetic state. Finally, as a long term goal in our work, we want to study the interaction of the genes whose interplay results in the obese-diabetic syndrome. As each gene that determines small dense LDL, the atherosclerotic factor and the diabetogenic factor is defined, we will construct congenics by placing one allele of each gene on a C57BL/6 background. The construction of congenic strains will greatly facilitate future studies on the physiology and the mechanism of action of each gene. Our finding of a mouse model that displays many characteristics of human ATHS phenotype. will make it possible to answer many questions that cannot be resolved in the human system.

小而密的低密度脂蛋白 (LDL) 的表型似乎 在人类动脉粥样硬化和糖尿病中发挥重要作用。最多 人类糖尿病患者体内有小而密的低密度脂蛋白颗粒。此外，人类 已经发现了决定小密集低密度脂蛋白表型的基因。这 导致异常表型的等位基因发生在大约 30% 个人并与上半身肥胖、胰岛素有关 抵抗力增加，患心脏病的风险增加 3 倍。人类 动脉粥样硬化易感性基因被命名为 ATHS，我们刚刚 将此基因映射到人类 19 号染色体上或非常接近该基因 低密度脂蛋白受体。 本拨款提案的目的是确定并描述 小鼠中负责小表型的遗传因素 LDL 并研究其与其他遗传因素的相互作用 控制动脉粥样硬化、糖尿病和肥胖。首先我们将 确定决定小 LDL 产生的遗传因素 C57BL/Ks 糖尿病小鼠。如果我们确定了该基因，我们就会对其进行测序 并表征导致小而密 LDL 的突变。第二，我们 想要确定小密集 LDL 基因型之间的关系 以及 BKs 菌株中发现的致糖尿病和致动脉粥样硬化因子。 也就是说，我们将确定小密集 LDL 的基因是否与 致动脉粥样硬化或致糖尿病因素是相关的，甚至是相同的 基因。例如，我们是否应该发现低密度脂蛋白和致动脉粥样硬化 因子是相同的基因，这将首次直接表明， 低密度脂蛋白可以导致动脉粥样硬化。 第三，我们计划 确定小密集 LDL 表型与 BK 中肥胖糖尿病综合征的其他表型特征。 特别是，我们想回答小 LDL 是否 表型取决于糖尿病状态。最后，从长远来看 我们工作的目标是研究基因之间的相互作用 相互作用导致肥胖-糖尿病综合征。 由于每个基因 决定小密度低密度脂蛋白、动脉粥样硬化因子和 定义了糖尿病致病因素，我们将通过放置来构建同类 C57BL/6 背景上每个基因的一个等位基因。的建设 同源菌株将极大地促进未来的研究 每个基因的生理学和作用机制。 我们发现了一种具有许多特征的小鼠模型 人类 ATHS 表型。将使回答许多问题成为可能 这是人类系统无法解决的。