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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

基本信息

批准号：
7502092
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
项目类别：
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/7502092
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

项目摘要

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。ATP结合盒转运体ABCA1介导巨噬细胞泡沫细胞向apoA-1的胆固醇外排。ABCA1从细胞表面运输到晚期核内体，并与neemann - pick C1 （NPC1）分子合作，促进胆固醇从核内体向apoA-1的外排。ApoE-/- npc1 -/-小鼠表现出动脉粥样硬化加速、管腔血栓形成和内侧糜烂。NPC1-/-或修饰的LDL负载巨噬细胞增加Cathepsin K的表达和分泌，这与内体中胆固醇的积累有关，这可以通过LXR激活、ABCA1的诱导和胆固醇向apoA-1的外排而部分逆转。内体胆固醇积累似乎导致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受体激活因子）结合所诱导的，需要激活p38 MAP激酶。在Aim1中，我们将进一步定义不同内体胆固醇库、诱导CatK和逆转ABCA1变异与细胞内运输改变之间的关系。我们将评估内体或膜筏中的胆固醇积累导致RANK和下游信号通过p38 MAP激酶自动激活以诱导CatK的假设。在Aim 2中，我们将对ApoE-/- npc1 -/-小鼠进行神经系统疾病的转基因拯救，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-/-小鼠产生内侧糜烂和管腔血栓形成的必要和充分的假设。我们还将在apoE-/- NPC1-/-小鼠中进行巨噬细胞特异性的p38 MAP激酶KO，以评估p38 MAP激酶信号增强的其他潜在下游效应。最后，我们将通过腺病毒- apoa -1表达和LXR激活来确定ApoE-/- npc1 -/-小鼠动脉粥样硬化及其并发症是否可以逆转。这些研究有助于阐明特定细胞区室内巨噬细胞中胆固醇积累与诱导CatK表达之间的机制联系，从而导致基质降解和动脉粥样硬化斑块的分解。这些机制的见解可能为易损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。