Mechanisms of Defective Efferocytosis in Atherosclerosis

动脉粥样硬化中细胞作用缺陷的机制

• 批准号: 8389888
• 负责人: Ira A Tabas
• 金额: $ 38.08万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8389888
• 关键词: Acute; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Apolipoproteins B; Apoptosis; Apoptotic; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Blood Platelets; CD36 gene; Cause of Death; Cell Maturation; Cells; Clinical; Complement; Coupled; Data; Development; Disease; Etiology; Event; Fatty acid glycerol esters; Granulocyte-Macrophage Colony-Stimulating Factor; Heart Diseases; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Laboratories; Lesion; Leukocytes; Link; Lipoprotein (a); Maps; Mediating; Molecular; Molecular Genetics; Mus; Myelogenous; Myocardial Infarction; NADPH Oxidase; Necrosis; Organ; Pathologic; Pathway interactions; Play; Population; Process; Reactive Oxygen Species; Role; Signal Transduction; Site; Societies; Staging; Stroke; Sudden Death; T-Cell Activation; Testing; Thrombosis; Toll-Like Receptor 2; Vascular Diseases; Vascular blood supply; apolipoprotein Lp(a+); base; design; feeding; genetic manipulation; in vivo; macrophage; monocyte; mouse model; mutant; novel therapeutics; prevent; receptor

DESCRIPTION (provided by applicant): A key event in atherothrombotic vascular disease is the conversion of subclinical lesions to disrupted plaques that trigger acute lumenal thrombosis. The PI's laboratory is focused on cellular and molecular processes involved in a critical feature of dangerous plaques, the necrotic core, which contributes to inflammation, plaque disruption, and thrombosis. Necrotic cores arise from the apoptosis of advanced lesional macrophages coupled with defective phagocytic clearance, or "efferocytosis," of the apoptotic macrophages. The objective of this proposal is to elucidate mechanisms and consequences of defective efferocytosis in the two major populations of monocyte-derived cells in advanced atherosclerosis, macrophages and dendritic-like cells (DCs). Aim 1 will explore the hypothesis that ADAM17-mediated cleavage of the efferocytosis receptor MerTK in advanced lesional macrophages contributes to defective efferocytosis and plaque necrosis. Subaim 1A will explore in vitro and in vivo a new mechanism that leads to MerTK cleavage involving athero-relevant activators of a CD36/Toll-like receptor 2/NADPH oxidase/PKC4 pathway. One such activator is apolipoprotein(a), which associates with apoB to form lipoprotein(a) [Lp(a)] and is genetically associated with human CAD. Subaim 1B will first investigate the temporal and quantitative relationships between lesional sol-Mer and plaque stage in murine and human atheromata and then will test causation by using a mouse with non-cleavable MerTK, which we predict will be protected from defective efferocytosis and plaque necrosis during lesion progression. Aim 2 will explore the hypothesis that enrichment of atheromata with mature DCs (mDCs), which lose efferocytic capacity, contributes to defective efferocytosis and plaque necrosis. We have shown that areas of advanced plaques enriched in mDCs, like those enriched in macrophages, are located near areas of plaque necrosis and have even worse efferocytosis than macrophage-rich regions. Subaim 2A will test the hypothesis that MerTK cleavage in DCs leads to defective efferocytosis by promoting DC maturation through inflammatory signaling. Subaim 2B will first study the relationships among lesional DCs, efferocytosis, and plaque necrosis in human carotid atheromata and in plaques of fat-fed Ldlr-/- and Apoe-/- mice and will then test causation by assessing the effect of two genetic manipulations that suppress DC development or maturation-GM-CSF deficiency and DC MyD88 deficiency. Achieving the stated objective will provide critical information for understanding how necrotic cores form and may help in the design of new therapeutic strategies to prevent the clinical progression of atherosclerotic lesions.

描述（由申请人提供）：动脉粥样硬化血栓形成性血管疾病的一个关键事件是亚临床病变转化为破裂斑块，触发急性管腔血栓形成。PI的实验室专注于参与危险斑块的关键特征的细胞和分子过程，坏死核心，这有助于炎症，斑块破裂和血栓形成。坏死核心由晚期病变巨噬细胞的凋亡引起，伴有凋亡巨噬细胞的吞噬清除缺陷或“吞噬作用”。本研究的目的是阐明晚期动脉粥样硬化中单核细胞来源的两大细胞群巨噬细胞和树突状细胞（DCs）中缺陷性巨噬细胞增多的机制和后果。目的1将探讨在晚期病变巨噬细胞中，ADAM 17介导的红细胞增多症受体MerTK的切割导致缺陷性红细胞增多症和斑块坏死的假说。Subaim 1A将在体外和体内探索导致MerTK裂解的新机制，该机制涉及CD 36/Toll样受体2/NADPH氧化酶/PKC 4通路的动脉粥样硬化相关激活剂。一种这样的激活剂是载脂蛋白（a），其与apoB结合形成脂蛋白（a）[Lp（a）]，并且与人类CAD遗传相关。Subaim 1B将首先研究小鼠和人动脉粥样硬化中病变sol-Mer和斑块阶段之间的时间和定量关系，然后将使用具有不可裂解MerTK的小鼠检测因果关系，我们预测在病变进展期间将保护其免受缺陷性红细胞增多和斑块坏死的影响。目的2将探讨动脉粥样硬化与成熟的DCs（mDCs），失去了红细胞的能力，导致缺陷的红细胞和斑块坏死的富集的假设。我们已经表明，富集mDC的晚期斑块区域，如富集巨噬细胞的区域，位于斑块坏死区域附近，并且比富含巨噬细胞的区域具有更差的巨噬细胞增多症。Subaim 2A将检验以下假设：DC中的MerTK裂解通过炎症信号传导促进DC成熟而导致缺陷性红细胞增多。Subaim 2B将首先研究人颈动脉粥样硬化中以及脂肪喂养的Ldlr-/-和Apoe-/-小鼠斑块中的病变DC、红细胞增多症和斑块坏死之间的关系，然后通过评估两种抑制DC发育或成熟的遗传操作-GM-CSF缺乏和DC MyD 88缺乏的影响来测试因果关系。实现所述目标将为了解坏死核心如何形成提供关键信息，并可能有助于设计新的治疗策略以预防动脉粥样硬化病变的临床进展。