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）：动脉瘤血栓性血管疾病中的一个关键事件是将亚临床病变转化为破坏的斑块，引发急性腔体血栓形成。 PI的实验室重点是涉及危险斑块的关键特征的细胞和分子过程，坏死核心有助于炎症，斑块破坏和血栓形成。坏死核是由凋亡巨噬细胞的晚期病变巨噬细胞的凋亡以及吞噬细胞清除率或“ for吞作用”的凋亡。该建议的目的是阐明在晚期动脉粥样硬化，巨噬细胞和树突状细胞（DCS）中，单核细胞衍生细胞的两个主要细胞中有缺陷的肿瘤病的机制和后果。 AIM 1将探讨以下假设：ADAM17介导的晚期巨噬细胞中胞吐受体MERTK的裂解有助于有缺陷的肿瘤病和斑块坏死。 Subaim 1a将在体外探索和体内一种新机制，该机制导致MERTK裂解，涉及CD36/TOLL样受体2/NADPH氧化酶/PKC4途径的动脉粥样硬化活化剂。一种这样的激活剂是载脂蛋白（A），它与APOB相关联，形成脂蛋白（A）[LP（A）]，并且与人CAD遗传相关。 Subaim 1b将首先研究鼠和人类动脉瘤中病变溶液和斑块阶段之间的时间和定量关系，然后通过使用具有不可裂解的MERTK的小鼠来测试因果关系，我们预测我们将免受有缺陷的遭受效应和斑块坏死的影响在病变进展过程中。 AIM 2将探讨以下假设：失去常见性的成熟DC（MDC）的动脉瘤富集，导致缺陷的肿瘤病和斑块坏死。我们已经表明，像巨噬细胞一样富含MDC的晚期斑块区域位于斑块坏死区域附近，甚至比富含巨噬细胞的区域更糟糕。 Subaim 2a将检验以下假设：DC中的MERTK裂解通过通过炎症信号传导促进DC成熟而导致肿瘤的缺陷。 Subaim 2b将首先研究人类颈动脉瘤和脂肪喂养的LDLR - / - 和apoE-/ - 鼠标的病变DC，经吞作用和斑块坏死之间的关系，然后通过评估两种遗传操作的影响，这抑制了直流开发或成熟GM-CSF缺乏症和DC MyD88缺陷。实现既定目标将提供关键信息，以了解坏死核如何形成，并可能有助于设计新的治疗策略，以防止动脉粥样硬化病变的临床进展。