Macrophage Foam Cells, Cathepsins and Cholesterol Efflux

巨噬细胞泡沫细胞、组织蛋白酶和胆固醇流出

• 批准号: 7662427
• 负责人: ALAN richard TALL
• 金额: $ 52.95万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-07-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7662427
• 关键词: ATP-Binding Cassette Transporters; Adenoviruses; Anti-Inflammatory Agents; Anti-inflammatory; Aorta; Apolipoprotein A-I; Apolipoprotein E; Apolipoproteins; Area; Arterial Fatty Streak; Atherosclerosis; Binding; Blood Vessels; Brain; Breeding; Cathepsins; Cell membrane; Cell surface; Cholesterol; Complement component C1s; Cyclodextrins; Defect; Dominant-Negative Mutation; Endosomes; Felis catus; Foam Cells; Genes; Genetic; Golgi Apparatus; High Density Lipoproteins; Human; Lead; Lesion; Ligands; Link; Longitudinal Studies; Low-Density Lipoproteins; Lysosomes; Mannose; Medial; Mediating; Membrane; Mus; Mutation; Osteoclasts; Plasma; Prions; Receptor Activation; Recycling; Role; Signal Transduction; Smooth Muscle Myocytes; Surface; Thrombosis; Thrombus; Transgenes; Transgenic Organisms; Variant; atherogenesis; cathepsin K; cholesterol trafficking; inhibitor/antagonist; insight; knock-down; late endosome; macrophage; mitogen-activated protein kinase p38; mutant; nervous system disorder; novel; overexpression; oxidized low density lipoprotein; programs; promoter; receptor; receptor binding; research study; trafficking; trait

DESCRIPTION (provided by applicant): Plasma high density lipoprotein levels are inversely related to atherosclerosis and its complications. The ATP binding cassette transporter ABCA1 mediates cholesterol efflux from macrophage foam cells to apoA-1. ABCA1 trafficks from the cell surface to late endosomes and co-operates with the Niemann-Pick C1 (NPC1) molecule in promoting efflux of cholesterol from endosomes to apoA-1. ApoE-/-NPC1-/- mice display accelerated atherosclerosis, luminal thrombosis and medial erosion. NPC1-/- or modified LDL loaded macrophages have increased Cathepsin K expression and secretion, related to cholesterol accumulation in endosomes, and this is partly reversed by LXR activation, induction of ABCA1 and cholesterol efflux to apoA-1. Endosomal cholesterol accumulation seems to cause activation of a partial osteoclast differentiation program, similar to that induced by binding of RANK ligand to RANK (Receptor Activator of NFkB) on macrophages and requiring activation of p38 MAP kinase. In Aim1 we will further define the relationship between different endosomal cholesterol pools, induction of CatK and reversal by variants of ABCA1 with altered intracellular trafficking. We will evaluate the hypothesis that cholesterol accumulation in endosomes or membrane rafts leads to auto-activation of RANK and downstream signaling via p38 MAP kinase to induce CatK. In Aim 2 we will carry out a transgenic rescue of neurological disease in ApoE-/-NPC1-/- mice allowing longer term studies of atherosclerosis and its complications. We will introduce the CatK-/- trait into this background and overexpress the native CatK transgene in ApoE-/- mice in order to evaluate the hypothesis that CatK overexpression is necessary and sufficient to produce medial erosion and luminal thrombosis in ApoE-/- mice. We will also carry out a macrophage-specific KO of p38 MAP kinase in apoE-/- NPC1-/- mice to evaluate other potential downstream effects of augmented p38 MAP kinase signaling. Finally, we will determine if atherosclerosis and its complications are can be reversed in ApoE-/-NPC1-/- mice by adenovirus-apoA-1 expression and LXR activation. These studies should help to elucidate a mechanistic link between cholesterol accumulation in macrophages within specific cellular compartments and induction of CatK expression, leading to matrix degradation and breakdown of atherosclerotic plaques. These mechanistic insights may suggest new treatments for vulnerable human plaques such as LXR activators, CatK inhibitors or inhibitors of RANK signaling.

描述（由申请人提供）：血浆高密度脂蛋白水平与动脉粥样硬化及其并发症呈负相关。ATP结合盒转运蛋白ABCA 1介导胆固醇从巨噬细胞泡沫细胞流出至apoA-1。ABCA 1从细胞表面运输到晚期内体，并与尼曼-匹克C1（NPC 1）分子合作，促进胆固醇从内体流出到apoA-1。ApoE-/-NPC 1-/-小鼠显示加速的动脉粥样硬化、管腔血栓形成和中膜侵蚀。NPC 1-/-或修饰的LDL负载的巨噬细胞具有增加的组织蛋白酶K表达和分泌，这与内体中的胆固醇积累有关，并且这部分地被LXR激活、ABCA 1的诱导和胆固醇流出至apoA-1逆转。内体胆固醇蓄积似乎引起部分破骨细胞分化程序的激活，类似于RANK配体与巨噬细胞上的RANK（NF κ B受体激活剂）结合诱导的程序，需要激活p38 MAP激酶。在Aim 1中，我们将进一步确定不同的内体胆固醇池，CatK的诱导和ABCA 1变异体与细胞内运输改变的逆转之间的关系。我们将评估胆固醇在内体或膜筏中蓄积导致RANK自激活和下游信号转导通过p38 MAP激酶诱导CatK的假设。在目标2中，我们将在ApoE-/-NPC 1-/-小鼠中进行神经系统疾病的转基因拯救，从而允许对动脉粥样硬化及其并发症进行更长期的研究。我们将在此背景下引入CatK-/-性状，并在ApoE-/-小鼠中过表达天然CatK转基因，以评估CatK过表达是ApoE-/-小鼠中产生中膜糜烂和管腔血栓形成所必需和充分的假设。我们还将在apoE-/-NPC 1-/-小鼠中进行p38 MAP激酶的巨噬细胞特异性KO，以评估增强的p38 MAP激酶信号传导的其他潜在下游效应。最后，我们将确定动脉粥样硬化及其并发症是否可以逆转载脂蛋白E-/-NPC 1-/-小鼠的腺病毒apoA-1表达和LXR激活。这些研究应有助于阐明胆固醇在巨噬细胞内的积累和诱导CatK表达之间的机制联系，导致基质降解和动脉粥样硬化斑块的分解。这些机制的见解可能会提出新的治疗方法，如LXR激活剂，CatK抑制剂或RANK信号抑制剂的脆弱的人类斑块。