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: 8625990
• 负责人: NOBUYO MAEDA
• 金额: $ 60.13万
• 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 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625990
• 关键词: 129 Mouse; Affect; Animals; Aorta; Apolipoprotein E; Apolipoproteins; Area; Arteries; Atherosclerosis; Attention; Backcrossings; Blood Vessels; Blood flow; Branchial arch structure; Candidate Disease Gene; Cardiovascular Diseases; Chromosomes; Chromosomes, Human, Pair 1; Code; Complement; Complex; Congenic Strain; Deposition; Development; Developmental Process; Disease; Dyslipidemias; Family; Genes; Genetic; Genetic Crosses; Genetic Crossing Over; Genetic Determinism; Genome; Geometry; Gli2 protein; Goals; Grant; Growth; Heterogeneity; Homing; Human; Inbred Strain; Induced Mutation; Lesion; Life; Location; Maps; Mediating; Meiosis; Mus; Myocardial Infarction; Patients; Phosphorylation; Plant Roots; Population; Predisposition; Process; Quantitative Trait Loci; Race; Recombinants; Research; Risk; Risk Factors; Site; Stroke; Testing; Transgenes; Variant; Yeasts; Zinc Fingers; aortic arch; atherogenesis; clinically relevant; congenic; endodeoxyribonuclease SceI; endonuclease; genome wide association study; hemodynamics; male; mouse genome; novel strategies; nuclease; prevent; promoter; public health relevance; smoothened signaling pathway; tool

The overall goal of our research is to develop a deeper understanding of the genetic factors underlying dyslipidemia and atherosclerosis. Areas of complex blood flow develop plaques preferentially, and the influence of hemodynamics on plaque development has been discussed extensively. Evidence is also accumulating that atherosclerosis at different vascular locations can involve distinguishable risk factors, although little attention has been paid to genetic factors that influence the sites of plaque development. We have found that Apoe-/- mice with the 129S6 genetic background (129-apoE) are slower to develop plaques at the aortic root than are Apoe-/- mice with a C57BL/6J background (B6-apoE), yet the 129-apoE mice develop plaques more rapidly in the aortic arch. Our quantitative trait loci (QTL) mapping of an F2 population of Apoe-/- mice between these strains has identified two QTL peaks, Aa1 and Aa2 on chromosome 1, that influence the susceptibility of the aortic arch to develop lesions. QTL-Aa1 overlaps QTL-Ga1, a QTL that influences the geometry of aortic arch curvature. The aortic arch QTLs are distinct from those affecting aortic root lesions. These observations support our hypothesis that subtle differences in vessel formation during development influence the occurrence of atherosclerosis later in life. Specific Aim 1 will further refine the QTL-Aa1 and Aa2 maps using genetic crosses, congenics and genome comparisons of inbred strains, 129S6, C57BL6/J, DBA/2J, A/J and AKR. Specific Aim 2 will facilitate "targeted crossover" within QTL intervals. Identifying the genes that form a QTL is facilitated when a congenic region is subdivided by crossover during backcrossing. To accelerate this process, we will combine meiosis-specific expression of I-SceI, a homing endonuclease of yeast, with its recognition sequence inserted into candidate genes within the QTL regions. The atherogenic effects of the induced mutations and of the narrowed QTL intervals will be assessed on an apoE-null background. Specific Aim 3 will test whether variations in the Gli2 gene influence aortic arch geometry and atherosclerosis. Gli2 lies within the interval covered by our overlapping QTLs, Aa1 and Ga1, and it codes for a transcriptional factor that mediates the sonic hedgehog signaling important for many developmental processes, including remodeling of branchial arch blood vessels to form the aortic arch. Deciphering genetic factors that affect plaque initiation and growth at one location along the aorta but not at another location has direct clinical relevance. Gaining a better understanding of location-dependent plaque development is an important contribution to the long-term goal of preventing the disease or of treating it before it becomes life threatening.

我们研究的总体目标是更深入地了解潜在的遗传因素 血脂异常和动脉粥样硬化。复杂血流区域优先形成斑块， 血液动力学对斑块发展的影响已经被广泛讨论。证据也 累积到不同血管位置的动脉粥样硬化可能涉及可区分的风险因素， 尽管很少有人注意影响斑块形成部位的遗传因素。我们 已经发现，具有129 S6遗传背景（129-apoE）的Apoe-/-小鼠在100 ℃时发展斑块较慢， 与具有C57 BL/6 J背景的Apoe-/-小鼠（B6-apoE）相比，129-apoE小鼠的主动脉根部发育 我们对Apoe-/-的F2群体进行了数量性状基因座（QTL）定位， 这些品系之间的小鼠已经确定了两个QTL峰，1号染色体上的Aa 1和Aa 2， 主动脉弓易发生病变。QTL-Aa 1与QTL-Ga 1重叠，这是一个影响 主动脉弓曲率的几何形状。主动脉弓QTL与影响主动脉根部病变的QTL不同。 这些观察结果支持了我们的假设，即发育过程中血管形成的细微差异 会影响日后动脉粥样硬化的发生。 具体目标1将进一步完善QTL-Aa 1和Aa 2图谱使用遗传杂交，同源和基因组 对129 S6、C57 BL 6/J、DBA/2 J、A/J和AKR等5个自交系进行了比较。 具体目标2将促进QTL区间内的“靶向交叉”。识别形成QTL的基因 在回交过程中，当一个同源区域被交叉细分时，加速这一 我们将联合收割机结合酵母归巢核酸内切酶I-SceI的减数分裂特异性表达， 插入到QTL区域内的候选基因中的识别序列。动脉粥样硬化的影响， 将在apoE无效背景下评估诱导的突变和缩小的QTL间隔。 具体目标3将测试Gli 2基因的变异是否影响主动脉弓几何形状， 动脉粥样硬化Gli 2位于我们的重叠QTL Aa 1和Ga 1所覆盖的区间内，它编码 一种介导对许多发育重要的音刺猬信号的转录因子 过程，包括鳃弓血管重塑形成主动脉弓。 解读影响主动脉沿着某一位置斑块形成和生长的遗传因素， 另一个位置具有直接的临床相关性。更好地了解位置依赖性斑块 发展是对预防或治疗这一疾病的长期目标的重要贡献 以免危及生命