APOLIPOPROTEIN GENES AND LIPOPROTEIN METABOLISM

载脂蛋白基因和脂蛋白代谢

基本信息

批准号：
2217323
负责人：
JAN Leslie BRESLOW
金额：
$ 39.7万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-07-01 至 1996-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2217323
关键词：
apolipoproteins atherosclerosis blood lipoprotein metabolism cholesterol dietary lipid disease /disorder model disease /disorder proneness /risk family genetics gene expression gene mutation genetic manipulation genetic regulatory element genetically modified animals high density lipoproteins human genetic material tag human tissue hypertriglyceridemia intestines laboratory mouse linkage mapping molecular pathology nutrition related tag particle pathogenic diet transcription factor triglycerides

apolipoproteins atherosclerosis blood lipoprotein metabolism cholesterol dietary lipid disease /disorder model disease /disorder proneness /risk family genetics gene expression gene mutation genetic manipulation genetic regulatory element genetically modified animals high density lipoproteins human genetic material tag human tissue hypertriglyceridemia intestines laboratory mouse linkage mapping molecular pathology nutrition related tag particle pathogenic diet transcription factor triglycerides

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项目摘要

The overall goal of this grant is to understand how apolipoproteins control lipoprotein metabolism and by this mechanism influence atherosclerosis susceptibility. The apolipoprotein genes have now been isolated, sequenced, and mapped. Consequently, it is now possible to create genetically altered animals in which apolipoprotein genes are over or under expressed to test directly specific hypotheses about how apolipoproteins control lipoprotein metabolism. Specifically, we will study how the apo A-I and apo CIII genes regulate lipoprotein metabolism, particularly the levels of HDL and triglyceride-rich lipoproteins, and influence atherosclerosis susceptibility. We expect that the insights gained from these studies will be useful in understanding human lipoprotein disorders. The specific aims are: 1. Characterize the role of the apo A-1 gene in determining HDL metabolism and atherosclerosis susceptibility. 1a. To increase atherosclerosis susceptibility in the mouse by knocking out the endogenous apo A-I gene. 1b. To study the influence of HDL levels on atherosclerosis progression and regression. 1c. To test whether HDL levels influence tissue cholesterol metabolism. 1d. To define how apo A-1 influences particle size distribution, HDL CE and apo A-I FCR, and HDL-CETP interaction. 1e. To determine the cis and trans acting factors controlling intestinal expression of apo A-1. 2. Characterize the role of the apo CIII gene in regulating triglyceride-rich lipoprotein metabolism. 2a. To study the mechanism of hypertriglyceridemia and determine its effect on atherosclerosis susceptibility in human apo CIII transgenic mice. 2b. To examine the mechanism underlying the association of high triglycerides and low HDL cholesterol levels in human apo CIII transgenic mice. 2c. To determine whether mutations at the apo CIII gene locus play a role in human hypertriglyceridemia. 2d. To create an apo CIII deficient mouse and use it to determine how apo CIII influences lipoprotein metabolism.

这笔赠款的总体目标是了解载脂蛋白如何控制脂蛋白代谢，并通过这种机制影响动脉粥样硬化的敏感性。载脂蛋白基因现在已经隔离，测序和映射。因此，现在有可能创建载脂蛋白基因结束的遗传改变的动物或表达以直接测试有关如何直接测试特定的假设载脂蛋白控制脂蛋白代谢。具体来说，我们会的研究APO A-I和APO CIII基因如何调节脂蛋白代谢，特别是HDL和富含甘油三酸酯的脂蛋白的水平，以及影响动脉粥样硬化的敏感性。我们期望见解从这些研究中获得的收益将有助于理解人类脂蛋白疾病。具体目的是： 1。表征APO A-1基因在确定HDL中的作用代谢和动脉粥样硬化的敏感性。 1a。增加小鼠动脉粥样硬化的敏感性淘汰内源性apo a-i基因。 1B。研究HDL水平对动脉粥样硬化的影响进程和回归。 1C。测试HDL水平是否影响组织胆固醇代谢。 1d为了定义APO A-1如何影响粒径分布，HDL CE和APO A-I FCR和HDL-CETP相互作用。 1e。确定控制的顺式和反式作用因素 Apo A-1的肠表达。 2。表征Apo CIII基因在调节中的作用富含甘油三酸酯的脂蛋白代谢。 2a。研究高甘油三酯血症的机制并确定其对人Apo CIII转基因动脉粥样硬化易感性的影响老鼠。 2b。检查高缔合的机制人apo CIII转基因中的甘油三酸酯和低HDL胆固醇水平老鼠。 2C。确定Apo CIII基因基因座的突变是否播放在人高糖性血症中的作用。 2d。创建APO CIII缺陷鼠标并使用它来确定 Apo CIII如何影响脂蛋白代谢。