Mechanisms of Defective Efferocytosis in Atherosclerosis

动脉粥样硬化中细胞作用缺陷的机制

基本信息

批准号：
8575547
负责人：
Ira A Tabas
金额：
$ 39.2万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
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/8575547
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)M cell 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

项目摘要

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）：动脉粥样硬化血栓性血管疾病的一个关键事件是亚临床病变转变为引发急性管腔血栓形成的破坏斑块。 PI 的实验室专注于涉及危险斑块（坏死核心）关键特征的细胞和分子过程，该特征会导致炎症、斑块破坏和血栓形成。坏死核心是由晚期病变巨噬细胞的凋亡以及凋亡巨噬细胞的吞噬清除或“胞吞作用”缺陷引起的。该提案的目的是阐明晚期动脉粥样硬化中两个主要单核细胞衍生细胞群——巨噬细胞和树突状细胞（DC）中胞吞作用缺陷的机制和后果。目标 1 将探讨以下假设：ADAM17 介导的晚期病变巨噬细胞中胞吞作用受体 MerTK 的裂解导致胞吞作用缺陷和斑块坏死。 Subaim 1A 将在体外和体内探索一种导致 MerTK 裂解的新机制，涉及 CD36/Toll 样受体 2/NADPH 氧化酶/PKC4 途径的动脉粥样硬化相关激活剂。其中一种激活剂是载脂蛋白 (a)，它与 apoB 结合形成脂蛋白 (a) [Lp(a)]，并且与人类 CAD 具有遗传相关性。 Subaim 1B 将首先研究小鼠和人类动脉粥样斑块中病变 sol-Mer 与斑块阶段之间的时间和定量关系，然后使用具有不可切割 MerTK 的小鼠测试因果关系，我们预测该小鼠将免受有缺陷的胞吞作用和斑块坏死的影响在病变进展过程中。目标 2 将探讨以下假设：动脉粥样硬化斑块中成熟 DC（mDC）的富集会丧失胞吞能力，从而导致胞吞作用缺陷和斑块坏死。我们已经证明，富含 mDC 的晚期斑块区域，就像那些富含巨噬细胞的区域一样，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胞吞作用。 Subaim 2A 将检验这样的假设：DC 中的 MerTK 裂解通过炎症信号传导促进 DC 成熟，从而导致胞吞作用缺陷。 Subaim 2B将首先研究人类颈动脉粥样斑块以及脂肪喂养的Ldlr-/-和Apoe-/-小鼠斑块中病变DC、胞吞作用和斑块坏死之间的关系，然后通过评估两种基因操作的效果来测试因果关系抑制 DC 发育或成熟 - GM-CSF 缺乏和 DC MyD88 缺乏。实现既定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防止动脉粥样硬化病变的临床进展。