ABCA1/ABCG1 in myeloid populations and atherogenesis

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）的发病率呈反比关系，但这种关系的机制尚未完全了解。HDL的中枢抗动脉粥样硬化作用被认为是由从动脉粥样化巨噬细胞泡沫细胞到HDL或apoA-1的胆固醇流出介导的，该过程部分由ATP结合盒转运蛋白ABCA 1和ABCG 1介导。该项目的最新工作揭示了HDL和这些ABC转运蛋白的新功能：促进造血干细胞和祖细胞（HSPC）的胆固醇流出。来自HSPC的胆固醇流出在控制其对生长因子如IL-3和GM-CSF的增殖反应中具有重要作用。缺乏ABCA 1/G1的小鼠中HSPC的增殖导致白细胞增多、单核细胞增多和加速动脉粥样硬化。拟议的研究将检查这种增强增殖的机制，例如HSPC上GM-CSF/IL-3受体的细胞表面水平增加。摩尔博士将研究micro-RNA-33在介导生长因子抑制ABCA 1/G1中的可能作用。此外，这些研究将采用最近开发的Abca 1fl/flAbcg 1fl/fl小鼠，这些小鼠将与各种表达Cre的菌株杂交，以检查泡沫细胞、HSPC和树突状细胞中转运蛋白表达降低在加速动脉粥样硬化产生中的单独作用。与Fisher博士合作，我们还将使用这些小鼠模型来研究转运蛋白在促进动脉粥样硬化消退中的作用。 公共卫生相关性：我们提出了一种新的机制，HDL的动脉粥样硬化保护作用，其中HDL与ABC转运蛋白共同作用，促进胆固醇流出，抑制造血干细胞的增殖。这些研究可能有助于建立干细胞增殖与动脉粥样硬化相关的白细胞增多和单核细胞增多之间的联系。

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.