Apolipoprotein Genes and Atherogenesis in Animals

动物载脂蛋白基因和动脉粥样硬化形成

• 批准号: 8121297
• 负责人: NOBUYO MAEDA
• 金额: $ 3.07万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121297
• 关键词: Accounting; Adipocytes; Adipose tissue; Affect; Alleles; Animals; Apolipoprotein E; Apolipoproteins; Arteries; Atherosclerosis; Award; Body mass index; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Collaborations; Development; Disease; Dominant-Negative Mutation; Dyslipidemias; France; Gender; Gene Expression Regulation; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genetic Variation; Grant; High Density Lipoproteins; Human; Human Genetics; Hypertension; Inbred Strain; Incidence; Indium; Individual; Insulin Resistance; Life Style; Link; Lipoproteins; Location; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Maps; Metabolic syndrome; Mus; Obesity; Overweight; PPAR gamma; PPARG gene; Patients; Peroxisome Proliferator-Activated Receptors; Plant Roots; Plasma; Play; Population; Problem Solving; Protein Isoforms; Reporting; Research; Risk; Role; Series; Sex Characteristics; Site; Societies; Syndrome; Testing; Variant; adipocyte differentiation; aortic arch; apolipoprotein E-4; atherogenesis; cardiovascular disorder risk; cardiovascular risk factor; defined contribution; gender preference; genetic variant; high risk; hypercholesterolemia; in vivo; insight; lipid biosynthesis; mouse model; preference; public health relevance; research study; tool

DESCRIPTION (provided by applicant): The overall objective of this project is to develop a deeper understanding of the genetic variants underlying dyslipidemia and atherosclerosis. We will use mouse genetics as a tool to gain insight into human atherogenesis where the effects of the common human polymorphic variants are small at the level of individuals but large at the population level. For example, increased plasma low-density lipoproteins (LDL) and an increased risk of developing atherosclerosis are associated in humans with the three common alleles of APOE in the order of APOE*4 > APOE*3 > APOE*2. Toward solving the mechanisms underlying this association, we have generated mice expressing human apoE2, E3 or E4 in place of mouse apoE. These mice recapitulate the human results, but only when they also express high levels of the human LDL receptor (LDLR). Thus these humanized mice have revealed an important interplay between the apoE isoforms and LDLR levels in a manner previously not suspected. Because the apoE polymorphism is so common and its associated risks are so definite, our first two specific aims will use the humanized mice to better define the differential contributions of the apoE-isoforms to the risk of developing atherosclerosis and the metabolic syndrome (an aggregation of obesity, dyslipidemia, insulin resistance, and hypertension). Specific Aim 1 will test the hypothesis that interactions between the apoE isoforms and LDLR play an important role in adipocyte function and thence in atherogenesis using experiments in cultured preadipocytes and in vivo experiments in a mouse genetic model of obesity. Specific Aim 2 will test the hypothesis that the human variants of apoE interact with variants of peroxisome proliferator-activated receptor gamma (PPAR?) in determining the functionality of adipocytes and thence the development of the metabolic syndrome. Strain 129S6 and C57BL/6J mice that are Apoe-/- develop plaques preferentially at different sites (the aortic root and the aortic arches), at different rates, and with differences in the effects of gender. They also have strain-specific differences in the geometry of their aortic arches. Our Specific Aim 3 will explore a new direction of atherosclerosis studies-namely the identification of genetic factors influencing the locations of plaque development. We will use SNP analysis to map strain-specific genetic factors that influence the site preference and gender effects, and test whether strain differences in arterial geometry play a role in the location of plaques. Identifying genetic loci that affect these variables should provide new and important tools for better identifying individuals at high risk of atherosclerosis before the disease has developed. PUBLIC HEALTH RELEVANCE: Cardiovascular diseases resulting from clogging of the arteries (atherosclerosis) account for a large proportion of sickness and deaths in advanced societies. The risk of developing atherosclerosis in individuals is determined by genetic and life-style factors. Using mouse genetics as a tool, we aim to determine how some common human genetic differences affect atherosclerosis and how the genetic effects are influenced by being overweight and by other common gene variants.

描述（由申请人提供）：本项目的总体目标是深入了解血脂异常和动脉粥样硬化的遗传变异。我们将使用小鼠遗传学作为一种工具来深入了解人类动脉粥样硬化形成，其中常见的人类多态性变体的影响在个体水平上很小，但在群体水平上很大。例如，血浆低密度脂蛋白（LDL）增加和动脉粥样硬化风险增加与人类APOE的三种常见等位基因相关，顺序为APOE*4 > APOE*3 > APOE*2。为了解决这种关联的机制，我们已经产生了表达人apoE 2，E3或E4代替小鼠apoE的小鼠。这些小鼠重现了人类的结果，但只有当它们也表达高水平的人LDL受体（LDLR）时。因此，这些人源化小鼠揭示了apoE亚型和LDLR水平之间的重要相互作用，其方式以前未被怀疑。由于apoE多态性是如此常见，其相关风险是如此明确，我们的前两个具体目标将使用人源化小鼠来更好地定义apoE亚型对动脉粥样硬化和代谢综合征（肥胖、血脂异常、胰岛素抵抗和高血压的聚集）风险的不同贡献。具体目标1将使用培养的前脂肪细胞实验和肥胖小鼠遗传模型中的体内实验来检验apoE亚型和LDLR之间的相互作用在脂肪细胞功能中起重要作用并因此在动脉粥样硬化形成中起重要作用的假设。具体目标2将测试的假设，即人类的apoE变异体与过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体？）在确定脂肪细胞的功能性和由此代谢综合征的发展方面。Apoe-/-的品系129 S6和C57 BL/6 J小鼠优先在不同部位（主动脉根和主动脉弓）以不同的速率发展斑块，并且性别效应存在差异。它们的主动脉弓的几何形状也有应变特异性差异。我们的特定目标3将探索动脉粥样硬化研究的新方向，即识别影响斑块发展位置的遗传因素。我们将使用SNP分析来绘制影响位点偏好和性别效应的菌株特异性遗传因素，并测试动脉几何形状的菌株差异是否在斑块的位置中发挥作用。确定影响这些变量的遗传位点应该提供新的和重要的工具，以更好地识别个体动脉粥样硬化的高风险之前，疾病已经发展。公共卫生关系：在发达社会中，由动脉阻塞（动脉粥样硬化）引起的心血管疾病占疾病和死亡的很大比例。个体发生动脉粥样硬化的风险由遗传和生活方式因素决定。使用小鼠遗传学作为工具，我们的目标是确定一些常见的人类遗传差异如何影响动脉粥样硬化，以及遗传效应如何受到超重和其他常见基因变异的影响。