REGULATION OF APOB SECRETION IN INBRED MOUSE STRAINS

血浆载脂蛋白B(Apo B100)升高和低 密度脂蛋白(LDL)与动脉粥样硬化的高风险相关 冠心病，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 (极低密度脂蛋白)来自肝脏，是两种血浆的必需蛋白质成分 极低密度脂蛋白和低密度脂蛋白。载脂蛋白B的过度生产是家族性 混合性高脂血症(FCHL)--一种遗传异质性的常见病 基础。遗传学研究表明，血浆载脂蛋白B水平受 未知的主基因。研究人员推测，血浆载脂蛋白B水平 部分受控于含载脂蛋白B的脂蛋白的分泌速度， 这是受基因控制的。探讨血浆载脂蛋白B的遗传基础 水平，我们选择只在肝脏中使用人类载脂蛋白B。这个 初步研究提供了肝B-100基因控制的证据 分泌导致F1代人载脂蛋白B水平的变化 同源HuBTg与各种近交系小鼠的杂交。进一步 对C57BL/6与129/Sv杂交的遗传研究发现了两个新的 主要数量性状基因座(QTL)(命名为载脂蛋白B调节基因座)， 解释了血浆中载脂蛋白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个 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，影响 参与载脂蛋白B组装和分泌的途径 脂蛋白，是FCHL的一个强有力的候选基因。它也是一种潜在的 治疗干预的目标。这些目标将通过 遵循目标。目标1：部分同源基因的产生和特征 含有调节血浆人载脂蛋白的染色体间隔的HuBTg小鼠系 B级。将使用特定的繁殖策略来生成 FING的区间特异性部分同源基因系(即，初始同源基因) 测绘和生化特征。目标2：高分辨率地形图 使用区间特有的包含主要载脂蛋白B调节基因的区间 初生的先天基因。初生的同源系对遗传的影响较大 将选择血浆载脂蛋白B水平进行精细定位。目标3：身份识别 以及在关键间隔内对包含 载脂蛋白B调节基因座。包含关键间隔的BAC重叠群将是 分析并鉴定了成绩单。候选基因的等位基因变异 将被确定并测试它们的功能意义。

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.