Pathophysiological Activities of Oxidized Phospholipids

氧化磷脂的病理生理活性

• 批准号: 7840709
• 负责人: EUGENE A PODREZ
• 金额: $ 21.99万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7840709
• 关键词: Accounting; Acute; Address; Adhesions; Affinity; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Binding; Biological Assay; Blood Circulation; Blood Platelets; CD36 gene; Calcium; Cell Communication; Cells; Chimeric Proteins; Cholesterol; Complex; Coronary; Data; Development; Endothelial Cells; Equilibrium; Event; Family; Generations; Goals; High Density Lipoproteins; In Vitro; Integrins; Knockout Mice; Knowledge; Lecithin; Ligands; Lipids; Lipoproteins; Mediating; Molecular; Molecular Weight; Mus; Mutate; P-Selectin; Pathway interactions; Peptides; Phospholipids; Phosphotransferases; Physiological; Platelet Activation; Platelet aggregation; Play; Process; Proteins; Recombinants; Research Personnel; Role; Rupture; Senile Plaques; Signal Transduction; Specificity; Staging; Structure; Surface; Testing; Thrombosis; acute coronary syndrome; atherogenesis; base; essential phospholipids; hypercholesterolemia; in vivo; inhibitor/antagonist; macrophage; member; monocyte; novel; oxidation; oxidized lipid; oxidized low density lipoprotein; programs; receptor; scavenger receptor

DESCRIPTION (provided by applicant): Recent studies indicate that platelet activation plays an important role in all stages of atherosclerotic lesion formation: initiation, progression, stability and thrombosis triggered by plaque rupture. Another event that is critical for the development of atherosclerosis is the generation of biologically active lipids via oxidation of lipoproteins. Considerable evidence has shown that specific oxidized phospholipids are generated in vivo and play a significant role in atherosclerosis. We have recently identified a physiologically relevant mechanism of lipoprotein oxidation and have found that the scavenger receptor CD36 is a major receptor responsible for the recognition of oxidized lipoproteins. A novel structurally conserved family of oxidized choline glycerophospholipids (oxPCcd36) in oxidized lipoproteins serves as high affinity ligands for CD36. oxPCcd36 is generated in vivo, and is enriched in atherosclerotic lesions . oxPCcd36 binds to platelets and induces platelet activation. Scavenger receptors type B (CD36 and SR-BI) appear to be involved. We hypothesized that platelets recognize oxPCcd36 via these receptors and this interaction leads to platelet activation in vivo. This activation could account for the platelet-monocyte and platelet-endothelial cell interaction in the initial stages of atherosclerosis development and for thrombogenicity of the lipid-rich core of plaque. The long-term goal of this proposal is to assess the molecular and cellular mechanisms of platelet interactions with oxPCcd36 and their role in the process of atherogenesis and thrombosis. The Specific Aims are: Aim I. To assess the mechanism by which platelet recognize oxPCcd36 and to determine the role of scavenger receptors type B in this process, a) We will characterize the specificity of oxPCcd36 recognition by platelets and receptors involved, b) We will identify the structural motifs of oxidized phospholipids that are essential for the binding to CD36. c) We will determine the molecular requirements for CD36 to recognize oxPCcd36- Aim II. To assess the physiological and pathophysiological consequences of the interaction of oxPCcd36 and platelets as related to platelet adhesion, activation, aggregation, and monocyte recruitment. We will study whether oxPCcd36 induces platelet activation and adhesion as assessed by a variety of assays. We will test whether SR-BI mediated interaction with HDL plays a role in platelet activation. We will test whether platelet activation by oxPCcd36 will induce the formation of platelet-monocyte aggregates. We will further determine whether platelets in such aggregates can activate monocytes. Aim III. We will seek to obtain evidence that oxPCcd36 can induce platelet activation via CD36 in vivo. We will assess whether oxPCcd36 are able to induce platelet activation and formation of platelet-monocyte aggregates in vivo. We will study the role of scavenger receptors type B in effects of oxPCcd36 in vivo in conditions of hypercholesterolemia. Collectively, the data obtained from this study should provide new information about the role of CD36 in development of atherosclerosis and acute coronary events.

描述（由申请人提供）：最近的研究表明，血小板激活在动脉粥样硬化病变形成的所有阶段都起着重要作用：由斑块破裂触发的起始，进展，稳定性和血栓形成。对于动脉粥样硬化发展至关重要的另一个事件是通过氧化脂蛋白产生生物活性脂质。大量证据表明，特定的氧化磷脂是在体内产生的，并在动脉粥样硬化中起重要作用。我们最近确定了一种与生理相关的脂蛋白氧化机制，发现清道夫受体CD36是负责识别氧化脂蛋白的主要受体。一种新型的结构保守的氧化胆碱甘油磷脂（OXPCCD36）的氧化脂蛋白中的家族是CD36的高亲和力配体。 OXPCCD36在体内产生，并富含动脉粥样硬化病变。 OXPCCD36与血小板结合并诱导血小板激活。 B型（CD36和SR-BI）似乎涉及清道夫受体。我们假设血小板通过这些受体识别OXPCCD36，这种相互作用导致体内血小板激活。这种激活可以解释血小板 - 单细胞和血小板 - 内皮细胞的相互作用，在动脉粥样硬化发育的初始阶段以及斑块富含脂质的核心的血栓形成性。该提案的长期目标是评估血小板与OXPCCD36相互作用的分子和细胞机制及其在动脉粥样硬化和血栓形成过程中的作用。具体目的是：目标I。为了评估血小板识别OXPCCD36的机制，并确定B型在此过程中的寻宝受体的作用，a）我们将表征涉及的血小板和受体识别OXPCCD36识别的特异性，b）我们将确定氧化磷脂的结构性基序，这些磷脂具有对粘合物的必要性cd36。 c）我们将确定CD36识别OXPCCD36-AIM II的分子需求。评估OXPCCD36和血小板相互作用的生理和病理生理后果与血小板粘附，激活，聚集和单核细胞募集有关。我们将研究OXPCCD36是否诱导通过多种测定法评估的血小板激活和粘附。我们将测试SR-BI介导的与HDL的相互作用是否在血小板激活中起作用。我们将测试OXPCCD36的血小板激活是否会诱导血小板 - 单细胞聚集体的形成。我们将进一步确定此类聚集体中的血小板是否可以激活单核细胞。目标三。我们将寻求获得证据表明OXPCCD36可以通过体内CD36诱导血小板激活。我们将评估OXPCCD36是否能够诱导体内血小板激活和血小板 - 单细胞聚集体的形成。我们将研究B型的清除剂受体在高胆固醇血症疾病中OXPCCD36在体内影响的作用。从本研究中获得的数据总的来说，应提供有关CD36在动脉粥样硬化和急性冠状动脉事件发展中的作用的新信息。