Pathophysiological Activities of Oxidized Phospholipids

氧化磷脂的病理生理活性

• 批准号: 6925309
• 负责人: EUGENE A PODREZ
• 金额: $ 30.6万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6925309
• 关键词: atherosclerosis; clinical research; high density lipoproteins; human subject; hypercholesterolemia; laboratory mouse; oxidized lipid; phospholipids; platelet activation; platelet aggregation; receptor binding; 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，血小板活化在动脉粥样硬化病变形成的各个阶段都起着重要作用：起始、进展、稳定和斑块破裂引发的血栓形成。另一个对动脉粥样硬化的发展至关重要的事件是通过脂蛋白氧化产生生物活性脂质。大量证据表明，体内产生特异性氧化磷脂，并在动脉粥样硬化中发挥重要作用。我们最近已经确定了脂蛋白氧化的生理相关机制，并发现清道夫受体CD36是负责识别氧化脂蛋白的主要受体。氧化脂蛋白中一个新的结构保守的氧化胆碱甘油磷脂家族（oxPCcd36）作为CD36的高亲和力配体。oxPCcd36在体内产生，在动脉粥样硬化病变中富集。oxPCcd36结合血小板并诱导血小板活化。B型清道夫受体（CD36和SR-BI）似乎与此有关。我们假设血小板通过这些受体识别oxPCcd36，这种相互作用导致血小板在体内活化。这种激活可以解释动脉粥样硬化发展初期血小板-单核细胞和血小板-内皮细胞的相互作用，以及斑块富含脂质的核心的血栓形成性。本研究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。目的1：评估血小板识别oxPCcd36的机制，并确定B型清扫剂受体在这一过程中的作用，a)我们将表征血小板和相关受体识别oxPCcd36的特异性，B)我们将确定氧化磷脂的结构基元，这是与CD36结合所必需的。c)我们将确定CD36识别oxPCcd36- Aim II的分子要求。评估与血小板粘附、活化、聚集和单核细胞募集相关的oxPCcd36与血小板相互作用的生理和病理生理后果。我们将研究oxPCcd36是否诱导血小板活化和粘附，通过各种实验来评估。我们将测试SR-BI介导的与HDL的相互作用是否在血小板活化中起作用。我们将测试oxPCcd36激活血小板是否会诱导血小板单核细胞聚集体的形成。我们将进一步确定这种聚集的血小板是否能激活单核细胞。第三目标。我们将寻求oxPCcd36在体内通过CD36诱导血小板活化的证据。我们将评估oxPCcd36是否能够在体内诱导血小板活化和血小板-单核细胞聚集体的形成。我们将研究B型清道夫受体在体内高胆固醇血症条件下对oxpcd36的影响。总的来说，从这项研究中获得的数据应该为CD36在动脉粥样硬化和急性冠状动脉事件发展中的作用提供新的信息。