REGULATION OF APOB SECRETION IN INBRED MOUSE STRAINS

近交系小鼠品系中 APOB 分泌的调节

• 批准号: 6530714
• 负责人: LI-SHIN HUANG
• 金额: $ 42.44万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6530714
• 关键词: alleles; apolipoprotein B; artificial chromosomes; genetic mapping; genetic regulation; genetic strain; genetic susceptibility; inbreeding; laboratory mouse; low density lipoprotein; regulatory gene; very low density lipoprotein

Elevated plasma levels of apolipoprotein B (apo B100) and low density lipoprotein (LDL) are associated with a higher risk for atherosclerotic coronary heart disease, a leading cause of mortality in the industrialized world. Apo B is required for the secretion of very low-density lipoproteins (VLDL) from the liver and is the mandatory protein constituent of both plasma VLDL and LDL. Overproduction of apo B is a major characteristics of familial combined hyperlipidemia (FCHL), a prevalent disease with heterogeneous genetic basis. Genetic studies have shown that plasma apo B levels are controlled by unknown major genes. The investigators hypothesize that plasma apoB levels are controlled, in part by the secretion rate of apo B-containing lipoproteins, which is genetically regulated. To determine the genetic basis of plasma apo B levels, we have chosen to use the human apo B only in the liver. The preliminary studies provided evidence of genetic control of hepatic B-100 secretion resulting in varying plasma human apo B levels in F1 offspring from crosses between a congenic HuBTg and various inbred mouse strains. Further genetic studies in crosses between C57BL/6 and 129/Sv have identified two novel major quantitative trait loci (QTL) (designated apo B regulator loci), which account for a majority of genetic variance of plasma human apo B levels in these crosses. The long-term goal of the proposal is to clone and characterize one of the major apo B regulator genes. This gene will be a novel regulator affecting the pathways involved in the assembly and secretion of apo B-containing lipoproteins and is a strong candidate gene for FCHL. It is also a potential target for therapeutic intervention. The goals will be achieved through the following aims. Aim 1: Generation and characterization of partial congenic HuBTg mouse lines containing chromosomal intervals regulating plasma human apo B levels. Specific breeding strategies will be used to generate interval-specific partial congenic lines (i.e., incipient congenics) for fine mapping and biochemical characterization. Aim 2: High resolution mapping of the interval containing a major apo B regulator locus using interval-specific incipient congenics. The incipient congenic line with a greater effect on the plasma apo B levels will be selected for fine mapping. Aim 3: Identification and characterization of transcripts within the critical interval containing the apo B regulator locus. A BAC contig containing the critical interval will be analyzed and transcripts identified. Allelic variants for the candidate gene will be identified and tested for their functional significance.

载脂蛋白 B (apo B100) 血浆水平升高且血浆水平降低 密度脂蛋白（LDL）与动脉粥样硬化的较高风险相关 冠心病是工业化国家死亡的主要原因 世界。 Apo B 是极低密度脂蛋白分泌所必需的 （VLDL）来自肝脏，是血浆中必需的蛋白质成分 极低密度脂蛋白和低密度脂蛋白。 apo B 过量产生是家族性的一个主要特征 混合性高脂血症（FCHL）是一种具有异质性遗传的流行病 基础。遗传学研究表明血浆载脂蛋白 B 水平受以下因素控制 未知的主基因。研究人员假设血浆 apoB 水平 部分由含apo B脂蛋白的分泌率控制， 这是受基因调控的。确定血浆载脂蛋白 B 的遗传基础 水平，我们选择仅在肝脏中使用人类载脂蛋白 B。这 初步研究提供了肝脏 B-100 基因控制的证据 分泌导致 F1 后代血浆人载脂蛋白 B 水平发生变化 同源 HuBTg 和各种近交小鼠品系之间的杂交。更远 C57BL/6 和 129/Sv 杂交的遗传研究发现了两种新的 主要数量性状基因座 (QTL)（称为 apo B 调节基因座），其中 解释了血浆中人类载脂蛋白 B 水平的大部分遗传变异 这些十字架。 该提案的长期目标是克隆并表征其中一种 主要apo B 调节基因。该基因将成为影响 参与含apo B的组装和分泌的途径 脂蛋白，是 FCHL 的有力候选基因。这也是一个潜力股 治疗干预的目标。这些目标将通过 以下目标。目标 1：部分同源的生成和表征 含有调节血浆人apo的染色体间隔的HuBTg小鼠系 B级。将使用特定的育种策略来产生 区间特定的部分同系系（即初期同系系） 绘图和生化表征。目标 2：高分辨率映射 包含主要 apo B 调节基因座的区间，使用区间特异性 初期同源性。对后代影响较大的早期同类系 将选择血浆载脂蛋白 B 水平进行精细绘图。目标 3：识别 以及包含以下内容的关键间隔内转录本的表征 apo B 调节基因座。包含关键间隔的 BAC 重叠群将是 分析并识别转录本。候选基因的等位基因变体 将对其功能意义进行识别和测试。