REGULATION OF APOB SECRETION IN INBRED MOUSE STRAINS

血浆载脂蛋白B（apo B100）水平升高， 低密度脂蛋白（LDL）与动脉粥样硬化的高风险相关 冠心病是工业化国家死亡的主要原因， 世界载脂蛋白B是分泌极低密度脂蛋白所必需的 低密度脂蛋白（VLDL）来自肝脏，是血浆中的必需蛋白质成分， VLDL和LDL。载脂蛋白B的过度表达是家族性高脂血症的主要特征 混合性高脂血症（FCHL）是一种异质性遗传性高脂血症， 基础遗传学研究表明，血浆载脂蛋白B水平受 未知的主要基因研究人员假设血浆apoB水平与 部分受含载脂蛋白B的脂蛋白的分泌速率控制， 这是由基因控制的。探讨血浆载脂蛋白B的遗传基础 水平，我们选择仅在肝脏中使用人载脂蛋白B。的 初步研究提供了肝B-100基因控制的证据 分泌导致F1代后代血浆人载脂蛋白B水平不同， 同类HuBTg和各种近交系小鼠品系之间的杂交。进一步 在C57 BL/6和129/Sv之间的杂交中的遗传研究已经鉴定了两种新的 主要数量性状基因座（QTL）（指定载脂蛋白B调节基因座）， 解释了血浆人载脂蛋白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和表征其中一种 主要载脂蛋白B调节基因。该基因将成为一种新的调节因子， 参与载脂蛋白B的组装和分泌的途径 是FCHL的强候选基因。这也是一种潜在的 治疗干预目标。这些目标将通过以下途径实现： 的目标。目的1：部分同源基因的产生和表征 含有调节血浆人载脂蛋白的染色体间隔的HuBTg小鼠系 B水平。具体的育种策略将用于产生 间隔特异性部分同源系（即，初期同类）罚款 作图和生化表征。目标2：高分辨率测绘 使用区间特异性方法检测含有主要载脂蛋白B调节基因位点的区间 早期的先天遗传早期同源系对 选择血浆载脂蛋白B水平用于精细绘图。目标3：识别 和表征转录本的关键间隔内， apo B调节基因座。包含关键间隔的BAC重叠群将被 分析并鉴定成绩单。候选基因的等位基因变体 将确定并测试其功能意义。

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.