ABCG1 AND FOAM CELLS IN DIABETES

糖尿病中的 ABCG1 和泡沫细胞

• 批准号: 7294618
• 负责人: Catherine C Hedrick
• 金额: $ 25.77万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-04 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7294618
• 关键词: atherosclerosis; bone marrow transplantation; cholesterol; flow cytometry; genetically modified animals; glucose; hyperglycemia; insulin dependent diabetes mellitus; insulin sensitivity /resistance; laboratory mouse; macrophage; membrane transport proteins; pathogenic diet; protein structure function; site directed mutagenesis; transfection /expression vector

ABCG1 is a novel ABC transporter that is present on macrophages and is a primary regulator of cholesterol efflux from macrophages to HDL in reverse cholesterol transport. Major unresolved questions in the field of atherosclerosis are whether ABCG1 directly regulates macrophage foam cell formation and thus, whether ABCG1 significantly influences atherosclerosis development. We have recently discovered in our laboratory that ABCG1 expression is dramatically downregulated in diabetic mouse macrophages, and that this ABCG1 downregulation decreases macrophage cholesterol efflux, thereby increasing foam cell formation in diabetic mice. Incidence of atherosclerosis is accelerated in patients with both type 1 and Type 2 diabetes 1"10. Recent work by Peter Edwards and colleagues showed that mice lacking ABCG1 had significant lipid deposition in multiple tissues, including both macrophages and endothelial cells11. Although atherosclerosis studies have not yet been performed in the ABCG1-deficient mice, the phenotypic profile of gross lipid accumulation in the animals strongly suggests that ABCG1 will be an important regulator of atherosclerosis development. In the current application, we hypothesize that chronic hyperglycemia in diabetes decreases macrophaqe ABCG1 function and results in increased macrophage foam cell formation in vivo. We hypothesize that the reduction in macrophage ABCG1 function increases atherosclerosis in the setting of diabetes. We propose to study how glucose regulates ABCG1 expression and function in diabetes.

ABCG1是一种新型的ABC转运蛋白，存在于巨噬细胞上，是胆固醇的主要调节剂 从巨噬细胞到HDL的外排在反向胆固醇转运中。在领域的主要未解决问题 动脉粥样硬化是ABCG1是否直接调节巨噬细胞泡沫细胞的形成，因此是否是否会调节 ABCG1显着影响动脉粥样硬化的发展。我们最近在实验室发现了 在糖尿病小鼠巨噬细胞中，ABCG1表达大大下调，并且该ABCG1 下调减少巨噬细胞胆固醇外排，从而增加糖尿病的泡沫细胞形成 老鼠。 1型和2型糖尿病1“ 10患者，动脉粥样硬化的发病率是加速的。 彼得·爱德华兹（Peter Edwards）及其同事最近的工作表明，缺乏ABCG1的小鼠具有明显的脂质 在多个组织中的沉积，包括巨噬细胞和内皮细胞11。虽然动脉粥样硬化 研究尚未在ABCG1缺陷型小鼠中进行，这是总脂质的表型特征 在动物中积累的强烈表明ABCG1将是动脉粥样硬化的重要调节剂 发展。在当前应用中，我们假设糖尿病中的慢性高血糖降低 Macrophaqe ABCG1的功能并导致体内巨噬细胞泡沫细胞的形成增加。我们 假设巨噬细胞ABCG1功能的降低会增加动脉粥样硬化 糖尿病。我们建议研究葡萄糖如何调节糖尿病中ABCG1的表达和功能。