MODELS OF ATHEROSCLEROSIS BY TARGETED GENE DUPLICATION

研究：该研究旨在产生人类的动物模型 通过基因靶向治疗动脉粥样硬化，并使用这些动物模型， 研究，在分子水平上，增加分泌的作用 载脂蛋白B对动脉粥样硬化形成的影响。分泌 载脂蛋白B的含量受载脂蛋白的影响 B（载脂蛋白B）的产生、脂蛋白结构单元的可用性，以及 分泌率血浆载脂蛋白B水平升高 脂蛋白被认为在人和小鼠中是致动脉粥样硬化的。 具体目标1和2是增加小鼠的血浆脂蛋白水平 通过增加载脂蛋白B（apo B）和微粒体 甘油三酯转移蛋白（MTP）大亚基。这 正常基因的复制会导致产量的增加 通过基因打靶和同源重组， （Smithies和Kim，1994）。这些变种人有一个优势 多拷贝随机整合转基因模型是控制 基因座对基因表达的影响最后，具体目标三是 建立一个多基因小鼠模型， l和2.此外，我将研究是否每一个组合 载脂蛋白E缺乏的重复增加动脉粥样硬化病变 严重性。 环境：该机构完全致力于产生和 利用动物模型研究人类疾病。前田博士和史密斯博士a 合作者，负责许多小鼠模型的生成。 博士Maeda是最重要的研究人员之一， 动脉粥样硬化的基因靶向治疗。她的实验室位于 病理科的史密斯医生学员，学生， 两个实验室的技术人员共享实验室会议， 随时交流想法和实验经验。

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.