LXR-activated Genes and Lipid Homeostasis

LXR 激活基因和脂质稳态

• 批准号: 6758076
• 负责人: Peter A Edwards
• 金额: $ 29.73万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6758076
• 关键词: apoptosis; atherosclerosis; blood lipoprotein metabolism; clinical research; gene expression; gene interaction; gene targeting; genetically modified animals; homeostasis; human genetic material tag; human subject; laboratory mouse; lipid metabolism; lipid transport; macrophage; nuclear receptors; protein binding; protein isoforms; protein structure function; tissue /cell culture

This subproject will test hypotheses, generated in the current grant period, that relate to the role of LXR and LXR target genes in the control of lipid homeostasis, macrophage function and the development of atherosclerosis. In the current grant period, we identified a number of genes that are induced when macrophages are exposed to LXR ligands; these genes (>70 total genes) include ABCG1, ABCA1, ADRP (adipophilin), PLTP, syndecan-1 and Spa. The human ABCG1 gene was shown to be atypical; it utilizes five promoters and alternative splicing to produce >8 transcripts and 5 protein isoforms. We now propose to determine the function of ABCG1 by utilizing both gene targeting and human ABCG1 transgenic mice. These studies will be complemented by mechanistic studies and studies that aim to identify the functional partner of ABCG1. These approaches will allow us to test the novel hypothesis that ABCG1 isoforms heterodimerize to form functional transmembrane transporters and that these heterodimers affect lipid efflux from cells. In addition, we will determine the importance of other LXR target genes (some of which are listed below) that are thought to be involved in a number of critical events related to atherosclerosis. These genes are thought to be involved in intracellular lipid droplet formation (ADRP), lipoprotein binding/uptake to cells (syndecan-1), apoptosis (Spa), phospholipid transfer/lipoprotein metabolism (PLTP) etc. We will investigate the mechanisms of regulation of these, and other genes, and use various strategies (activation in vivo, generation of knock out and transgenic mice, bone marrow transplants etc) to elucidate the function of these genes in controlling lipid homeostasis and atherosclerosis.

该副本将测试与当前赠款期间产生的假设，该假设与LXR和LXR靶基因在控制脂质稳态，巨噬细胞功能和动脉粥样硬化的发展中的作用有关。在当前的赠款期间，我们确定了巨噬细胞暴露于LXR配体时诱导的许多基因。这些基因（> 70个总基因）包括ABCG1，ABCA1，ADRP（adipophilin），PLTP，Syndecan-1和Spa。人类ABCG1基因被证明是非典型的。它利用五个启动子和替代剪接产生> 8个转录本和5种蛋白质同工型。现在，我们建议通过利用基因靶向和人ABCG1转基因小鼠来确定ABCG1的功能。这些研究将由旨在确定ABCG1功能伙伴的机械研究和研究补充。这些方法将使我们能够测试ABCG1同工型的新假设 异二聚体形成功能性跨膜转运蛋白，并且这些异二聚体会影响细胞的脂质外排。此外，我们将确定其他LXR靶基因（其中一些列出的）的重要性，这些基因被认为与动脉粥样硬化有关的许多关键事件涉及。这些基因被认为与细胞内脂质液滴形成（ADRP），脂蛋白结合/摄取/摄取/摄取/吸收/摄取与细胞（Syndecan-1），凋亡（SPA），磷脂转移/脂蛋白代谢（PLTP）等。小鼠，骨髓移植等）以阐明这些功能 控制脂质稳态和动脉粥样硬化的基因。