MODELS OF ATHEROSCLEROSIS BY TARGETED GENE DUPLICATION

研究：这项研究旨在建立人类的动物模型 通过基因打靶导致动脉粥样硬化，并利用这些动物模型 在分子水平上研究分泌增加的作用 载脂蛋白B在动脉粥样硬化形成中的作用。分泌物 载脂蛋白B对载脂蛋白的影响 B(载脂蛋白B)的生产，脂蛋白构建块的可用性，以及 分泌率。含载脂蛋白B的血浆水平升高 脂蛋白在人类和小鼠中被认为是致动脉粥样硬化的。 特异性目标1和2是提高小鼠血浆脂蛋白水平 通过增加载脂蛋白B(ApoB)和微粒体的水平 甘油三酯转移蛋白(MTP)大亚基分别为。这 正常基因的复制将导致产量的增加。 通过基因打靶和同源重组 描述(Smithies和Kim，1994)。与这些突变体相比，这些突变体有一个优势 多拷贝随机整合转基因模型是对照 基因表达的基因座效应。最后，具体目标三是 建立具有特定目的的两个重复的多基因小鼠模型 L和2。此外，我还将检查各自的组合 载脂蛋白E缺乏的重复增加动脉粥样硬化病变 严肃性。 环境：这个机构完全致力于 使用人类疾病的动物模型。前田博士和史密斯博士，一位 合作者，负责许多鼠标模型的生成。 前田博士是最早的研究人员之一，他制作了 基因打靶导致的动脉粥样硬化。她的实验室就在同一间 我是病理科的史密斯医生。学员们，学生们， 来自两个实验室的技术人员共享实验室会议，并可以 容易交流思想和实验经验。

Research: The research is directed at generating animal models of human atherosclerosis by gene targeting and to use these animal models to study, at the molecular level, the role of increased secretion of apolipoprotein B-containing lipoproteins on atherogenesis. The secretion of apo B-containing lipoproteins is under the influence of apolipoprotein B (apo B) production, availability of lipoprotein building blocks, and the secretory rates. Elevated levels of plasma-apoB-containing lipoproteins are considered to be atherogenic in humans and mice. Specific aims 1 and 2 are to increase-plasma lipoprotein levels in mice by increasing the levels of apolipoprotein B (apoB) and microsomal triglyceride transfer protein (MTP) large subunit, respectively. This increased production will result from duplications of the normal genes at their natural loci by gene targeting and homologous recombination as described (Smithies and Kim, 1994). One advantage these mutants have over multiple-copy-random-integration transgenic models is the control of locus effects on gene expression. Finally, specific aim three is to create a polygenic mouse model with both duplications from specific aims l and 2. In addition, I will examine if the combination of each duplication with apoE deficiency increases atherosclerotic lesion severity. Environment: This institution is fully committed to the generation and use of animal models for human disease. Dr. Maeda and Dr. Smithies, a collaborator, are responsible for the generation of many mouse models. Dr. Maeda is one of the foremost researchers generating animal models of atherosclerosis by gene targeting. Her laboratory is located on the same floor as Dr. Smithies in the Department of Pathology. Trainees, students, and technicians from both laboratories share laboratory meetings and can readily exchange ideas and experimental experience.