ABCA1/ABCG1 in myeloid populations and atherogenesis

ABCA1/ABCG1 在骨髓细胞群和动脉粥样硬化形成中的作用

• 批准号: 8085576
• 负责人: ALAN richard TALL
• 金额: $ 40.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8085576
• 关键词: ATP-Binding Cassette Transporters; Antiatherogenic; Apolipoprotein A-I; Apolipoprotein E; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Cell Proliferation; Cell surface; Chemotaxis; Cholesterol; Clinical Research; Collaborations; Complex; Defect; Dendritic Cells; Dependovirus; Fc Receptor; Foam Cells; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor; Hematopoietic; Hematopoietic stem cells; High Density Lipoproteins; Human; Incidence; Infiltration; Inflammatory Response; Infusion procedures; Interleukin-3; Intervention; Knock-out; Knockout Mice; Lentivirus Vector; Lesion; Leukocytosis; Link; Lipids; Mediating; Membrane; MicroRNAs; Monocytosis; Mus; Myelogenous; Phenotype; Phospholipids; Plasma; Play; Population; Process; Production; Resolution; Retroviral Vector; Role; Signal Transduction; Stem cells; Testing; Therapeutic; Transgenes; Transplantation; Up-Regulation; Work; atherogenesis; macrophage; monocyte; mouse model; novel; promoter; protective effect; receptor; reconstitution; research study; response; stem

DESCRIPTION (provided by applicant): Plasma high density lipoproteins (HDL) have an inverse relationship to the incidence of atherosclerotic cardiovascular disease (CVD) but the mechanisms underlying this relationship are incompletely understood. A central anti-atherogenic effect of HDL is believed to be mediated by cholesterol efflux from atheromatous macrophage foam cells to HDL or apoA-1, a process mediated in part by the ATP binding cassette transporters ABCA1 and ABCG1. Recent work in this project has uncovered a new function of HDL and these ABC transporters: the promotion of cholesterol efflux from hematopoietic stem and progenitor cells (HSPCs). Cholesterol efflux from HSPCs has an important role in controlling their proliferative response to growth factors such as IL-3 and GM-CSF. Proliferation of HSPCs in mice lacking ABCA1/G1 leads to leukocytosis, monocytosis and accelerated atherosclerosis. The proposed studies will examine the mechanisms underlying this enhanced proliferation, such as increased cell surface levels of the GM-CSF/IL-3 receptor on HSPCs. A possible role of micro-RNA-33 in mediating growth factor suppression of ABCA1/G1 will be examined with Dr. Moore. Also, the studies will employ recently developed Abca1fl/flAbcg1fl/fl mice that will be crossed with various Cre-expressing strains to examine the separate roles of decreased transporter expression in foam cells, HSPCs and dendritic cells in the production of accelerated atherosclerosis. In collaboration with Dr. Fisher, we will also use these mouse models to examine the role of transporters in facilitating regression of atherosclerosis. PUBLIC HEALTH RELEVANCE: We are proposing a novel mechanism for the athero-protective effect of HDL in which HDL acting in conjunction with ABC transporters promotes cholesterol efflux and suppresses proliferation of hematopoietic stem cells. These studies will likely help to establish a link between stem cell proliferation and the well known leukocytosis and monocytosis associated with atherosclerosis.

描述（由申请人提供）：血浆高密度脂蛋白（HDL）与动脉粥样硬化性心血管疾病（CVD）的发病率呈负相关，但这种关系的机制尚不完全清楚。HDL的中心抗动脉粥样硬化作用被认为是由粥样硬化巨噬细胞泡沫细胞向HDL或apoA-1的胆固醇外溢介导的，这一过程部分由ATP结合盒转运体ABCA1和ABCG1介导。该项目最近的工作揭示了HDL和这些ABC转运蛋白的新功能：促进造血干细胞和祖细胞（HSPCs）的胆固醇外排。HSPCs的胆固醇外排在控制其对IL-3和GM-CSF等生长因子的增殖反应中起重要作用。在缺乏ABCA1/G1的小鼠中，HSPCs的增殖导致白细胞增多、单核细胞增多和动脉粥样硬化加速。拟议的研究将研究这种增殖增强的机制，例如HSPCs上GM-CSF/IL-3受体细胞表面水平的增加。Moore博士将研究微rna -33在介导ABCA1/G1生长因子抑制中的可能作用。此外，研究将使用最近开发的Abca1fl/flAbcg1fl/fl小鼠，将其与各种cre表达菌株杂交，以检查泡沫细胞，HSPCs和树突状细胞中转运蛋白表达减少在加速动脉粥样硬化产生中的单独作用。在与Fisher博士的合作中，我们还将使用这些小鼠模型来检查转运蛋白在促进动脉粥样硬化消退中的作用。