MECHANISMS OF LOW LEVELS OF APOLIPOPROTEIN B

低水平载脂蛋白 B 的机制

• 批准号: 6183768
• 负责人: FRANCINE K WELTY
• 金额: $ 17.62万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-15 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6183768
• 关键词: abetalipoproteinemias; apolipoprotein B; blood lipoprotein metabolism; cardiovascular disorder epidemiology; clinical research; family genetics; gene mutation; genetic polymorphism; genetically modified animals; human genetic material tag; human subject; laboratory mouse; nucleic acid sequence; stable isotope; very low density lipoprotein

DESCRIPTION: Elevated apoB levels are associated with an increased risk of coronary heart disease. Hypobetalipoproteinemia (HBLP) is characterized by apoB levels less than the 5 percentile. The applicant has sequenced mutations for truncated forms of apoB-67, apoB-55 and apoB-44.4 which causes HBLP, described a kindred from the Framingham Heart Study with HBLP due to an unidentified apoB gene mutation and purified apoB-67 containing lipoprotein particles. Heterozygous apoB-67 subjects have one normal allele making apoB-100; therefore, apoB levels would be predicted to be at least 50 percent of normal; however, they are 24 percent of normal. The applicant has shown that these lower than expected levels result from decreased production of VLDL apoB-100, LDL apoB-100 and apoB-67, increased catabolism of VLDL apoB-100, and increased direct removal of apoB-67 from VLDL. The applicant proposes to study mechanisms for these observations. Specific aim 1 is to locate the apoB gene mutation in the Framingham kindred. Specific aim 2 is to perform stable isotope studies in the apoB-55 and apoB-44.4 kindreds to determine if apoB metabolism for these shorter truncations is similar to that for apoB-67. In specific aim 3, apoB-100 synthesis will be studied in heterozygous apoB-70 transgenic mice. If it is 25-25 percent of normal litter mates, the mechanism for this reduction in apoB-100 levels will be studied in hepatocytes isolated from the transgenic mice. In specific aim 4, size and composition of VLDL will be compared in apoB-67 subjects and controls to determine if larger size or compositional changes account for the faster catabolism of VLDL apoB-100.

描述：apoB水平升高与以下风险增加相关： 冠心病 低β脂蛋白血症（HBLP）的特征是： 载脂蛋白B水平低于百分之五 申请人已测序 apoB-67、apoB-55和apoB-44.4的截短型突变， HBLP，描述了一个来自心脏病研究的HBLP家族， 未鉴定的apoB基因突变和纯化的apoB-67， 脂蛋白颗粒。 杂合子apoB-67受试者有一个正常等位基因 apoB-100;因此，apoB水平预计至少为50 正常值的24%，但正常值的24%。 申请人 这些低于预期水平的原因是， VLDL apoB-100、LDL apoB-100和apoB-67的产生， 的VLDL apoB-100，并增加apoB-67从VLDL的直接去除。 的 申请人建议研究这些观察的机制。 具体目标 1是在Frauplasty家系中定位apoB基因突变。 具体 目的2是对apoB-55和apoB-44进行稳定同位素研究。 动力学，以确定这些较短截短的apoB代谢是否 与apoB-67相似。 在具体目标3中，apoB-100的合成将是 在杂合apoB-70转基因小鼠中研究。 如果是25%-25%， 正常同窝仔，apoB-100水平降低的机制 将在从转基因小鼠分离的肝细胞中进行研究。 在 具体目4，将在apoB-67中比较VLDL的大小和组成 受试者和对照组，以确定较大的尺寸或成分变化 解释了VLDL apoB-100的更快催化。