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.

该子项目将测试在当前资助期内产生的假设，这些假设与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发展中的作用有关。在当前的资助期内，我们确定了当巨噬细胞暴露于LXR配体时会诱导的许多基因;这些基因（总共超过70个基因）包括ABCG 1、ABCA 1、ADRP（亲脂蛋白）、PLTP、syndecan-1和Spa。人类ABCG 1基因被证明是非典型的;它利用5个启动子和选择性剪接产生>8个转录物和5个蛋白质同种型。我们现在建议通过利用基因打靶和人ABCG 1转基因小鼠来确定ABCG 1的功能。这些研究将通过机制研究和旨在确定ABCG 1功能伙伴的研究来补充。这些方法将使我们能够测试新的假设，ABCG 1亚型 异二聚体形成功能性跨膜转运蛋白，且这些异二聚体影响脂质从细胞流出。此外，我们将确定其他LXR靶基因（其中一些在下面列出）的重要性，这些基因被认为参与了许多与动脉粥样硬化相关的关键事件。这些基因被认为参与细胞内脂滴形成（ADRP）、脂蛋白结合/摄取细胞（syndecan-1）、凋亡（Spa）、磷脂转运/脂蛋白代谢（PLTP）等。我们将研究这些基因和其他基因的调控机制，并使用各种策略（体内激活、产生敲除和转基因小鼠、骨髓移植等）来阐明这些基因的功能。 基因控制脂质稳态和动脉粥样硬化。