ABCA1/ABCG1 in myeloid populations and atherogenesis

描述(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，但这种关系背后的机制尚不完全清楚。高密度脂蛋白的中枢抗动脉粥样硬化作用被认为是通过胆固醇从动脉粥样硬化性巨噬细胞泡沫细胞流出到高密度脂蛋白或载脂蛋白A-1，这一过程部分是由三磷酸腺苷结合盒转运体ABCA1和Abcg1介导的。该项目最近的工作揭示了高密度脂蛋白和这些ABC转运体的一个新功能：促进胆固醇从造血干细胞和祖细胞(HSPC)流出。HSPC的胆固醇外流在控制其对IL-3和GM-CSF等生长因子的增殖反应中起着重要作用。在缺乏ABCA1/G1的小鼠体内，HSPC的增殖会导致白细胞增多、单核细胞增多和加速的动脉粥样硬化。拟议的研究将探讨这种促进增殖的机制，例如HSPC上GM-CSF/IL-3受体的细胞表面水平增加。微RNA-33在介导生长因子抑制ABCA1/G1中的可能作用将与摩尔博士一起研究。此外，这项研究还将利用最近开发的Abca1fl/flAbcg1fl/fl小鼠与各种表达Cre的菌株杂交，以检测泡沫细胞、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形成中的单独作用。在与Fisher博士的合作中，我们还将使用这些小鼠模型来研究转运蛋白在促进动脉粥样硬化消退中的作用。

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.