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: 7808208
• 负责人: NOBUYO MAEDA
• 金额: $ 2.97万
• 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/7808208
• 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）：该项目的总体目标是更深入地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异的影响在个体水平上很小，但在群体水平上却很大。例如，在人类中，血浆低密度脂蛋白 (LDL) 增加和发生动脉粥样硬化的风险增加与 APOE 的三个常见等位基因相关，顺序为 APOE*4 > APOE*3 > APOE*2。为了解决这种关联的机制，我们培育了表达人类 apoE2、E3 或 E4 的小鼠来代替小鼠 apoE。这些小鼠重现了人类的结果，但前提是它们也表达高水平的人类 LDL 受体 (LDLR)。因此，这些人源化小鼠以一种以前未曾怀疑的方式揭示了 apoE 同工型和 LDLR 水平之间的重要相互作用。由于 apoE 多态性如此常见且其相关风险如此明确，我们的前两个具体目标将使用人源化小鼠来更好地确定 apoE 同工型对发生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综合）风险的差异贡献。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的体内实验来检验以下假设：apoE 同工型和 LDLR 之间的相互作用在脂肪细胞功能中发挥重要作用，从而在动脉粥样硬化形成中发挥重要作用。具体目标 2 将检验以下假设：apoE 的人类变体与过氧化物酶体增殖物激活受体 γ (PPAR?) 的变体相互作用，以确定脂肪细胞的功能，从而确定代谢综合征的发展。 Apoe-/- 品系 129S6 和 C57BL/6J 小鼠在不同部位（主动脉根部和主动脉弓）优先形成斑块，速度不同，性别影响也不同。它们的主动脉弓几何形状也存在应变特异性差异。我们的具体目标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。识别影响这些变量的基因位点应该提供新的重要工具，以便在疾病发生之前更好地识别动脉粥样硬化高风险个体。公共卫生相关性：在先进社会中，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一部分。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，以及超重和其他常见基因变异如何影响遗传效应。