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: 7316299
• 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/7316299
• 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; Localized; Longitudinal Studies; Low-Density Lipoproteins; Lysosomes; Mannose; Medial; Mediating; Membrane; Mus; Mutation; Osteoclasts; Plasma; Prions; Protein Overexpression; Receptor Activation; Recycling; Role; Signal Transduction; Smooth Muscle Myocytes; Surface; Thrombosis; Thrombus; Transgenes; Transgenic Organisms; Variant; atherogenesis; cathepsin K; cholesterol trafficking; human MAPK14 protein; inhibitor/antagonist; insight; knock-down; late endosome; macrophage; mitogen-activated protein kinase p38; mutant; nervous system disorder; novel; 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(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。三磷酸腺苷结合盒转运体ABCA1介导胆固醇从巨噬细胞泡沫细胞外流到载脂蛋白A-1。ABCA1从细胞表面运输到晚期内体，并与Niemann-Pick C1(NPC1)分子合作，促进胆固醇从内体流出到apoA-1。APOE-/-NPC1-/-小鼠表现为动脉粥样硬化加速、管腔血栓形成和中膜侵蚀。NPC1-/-或修饰的低密度脂蛋白负载的巨噬细胞增加了组织蛋白酶K的表达和分泌，这与胆固醇在内体中的积聚有关，这一作用可被LXR激活、ABCA1诱导和胆固醇外流到apoA-1而部分逆转。内体胆固醇的积聚似乎引起部分破骨细胞分化程序的激活，类似于巨噬细胞上RANK配体与RANK(NFkB受体激活剂)结合并需要激活p38 MAP激酶所诱导的程序。在Aim1中，我们将进一步定义不同内体胆固醇池之间的关系，CatK的诱导以及ABCA1变异与细胞内转运改变的逆转之间的关系。我们将评估一种假说，即胆固醇在内体或膜筏中的积累导致RANK的自动激活，并通过p38 MAP激酶诱导CatK的下游信号。在目标2中，我们将在ApoE-/-NPC1-/-小鼠身上进行神经系统疾病的转基因挽救，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CatK-/-特性引入到这一背景中，并在ApoE-/-小鼠中过表达天然的CatK转基因基因，以评估CatK过表达对于ApoE-/-小鼠中膜侵蚀和管腔血栓形成的必要性和充分性的假说。我们还将在apoE-/-NPC1-/-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激酶信号的其他潜在下游效应。最后，我们将确定是否可以通过腺病毒-apoA-1的表达和LXR的激活来逆转ApoE-/-NPC1-/-小鼠的动脉粥样硬化及其并发症。这些研究应该有助于阐明巨噬细胞在特定细胞间隔内的胆固醇积聚和CatK表达诱导之间的机制联系，从而导致基质降解和动脉粥样硬化斑块的破裂。这些机制上的见解可能会为脆弱的人类斑块提供新的治疗方法，如LXR激活剂、CatK抑制剂或RANK信号抑制剂。