Proatherogenic properties of platelet fator 4

血小板因子 4 的促动脉粥样硬化特性

• 批准号: 7580982
• 负责人: Bruce S Sachais
• 金额: $ 38.48万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-07 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7580982
• 关键词: Adolescence; Aging; Applications Grants; Blood Platelets; China; Consensus; Country; Development; Discipline; Education; Educational Curriculum; Educational process of instructing; Gender Role; Grant; Health; Health Services; Human Rights; Income; Institution; International; Knowledge; Life Cycle Stages; Morbidity - disease rate; Phase; Policy Making; Property; Public Health Schools; Reproduction; Reproductive Health; Research; Research Personnel; Resources; Sex Behavior; Sexuality; Training; Training Programs; United States National Institutes of Health; Universities; Work; base; behavioral/social science; burden of illness; child bearing; clinical practice; continuing medical education; design; disability; health training; meetings; multidisciplinary; programs; skills; working group

DESCRIPTION (provided by applicant): Atherosclerosis is complex vascular disorder involving the interplay between inflammation, coagulation and lipid metabolism. There is increasing evidence that platelet activation but may play important roles in the initiation and/or expansion of atherosclerotic lesions. As platelets contain diverse modulators of inflammation, cell adhesion and endothelial activation, elucidating the mechanisms by which platelets promote atherogenesis may offer novel opportunities for intervention. My group has focused on the involvement of the platelet specific chemokine platelet factor 4 (PF4) in atherosclerosis. We have generated preliminary data in vivo that support the notion that PF4 is proatherogenic. Previous work from our laboratory has defined two receptor dependent pathways that may be responsible for PF4 atherogenicity. First, PF4 inhibits low density lipoprotein receptor (LDLR) dependent low density lipoprotein (LDL) degradation. This results in retention of LDL on the cell surface, which is prone to modification into oxidized LDL (ox-LDL). Second, PF4 activated NF-kB (a transcription factor involved in atherosclerosis and inflammation) via the LDL receptor related protein (LRP). The overriding hypothesis of this proposal is that PF4 activates one or both of these pathways to promote atherosclerotic lesion formation. We further posit that PF4 tetramers oligomerize in the presence of cell surface glycosaminoglycans (GAGs) before activation of the LDLR and/or LRP pathways. To test this hypothesis, we will study the effect of PF4 on atherosclerosis in vivo and elucidate its mechanism of action both in vivo and on vascular cells using in vitro model systems through three related Specific Aims: SA I: "Structural features of PF4 that contribute to proatherogenicity" will further dissect the details of these pathways in vitro, focusing on structural characteristics of PF4. SA II: "Characterize the effects of PF4 on lipoprotein metabolism and atherosclerosis in apoE-/- mice" will expand our characterization of apoE-/- mice lacking PF4, as well as to understand the implications of PF4 overexpression in apoE-/- mice. SA III: "Mechanism of PF4 proatherogenicity in vivo" will examine the importance of both the LDLR and LRP pathways for PF4 mediated atherogenesis. These studies will provide novel insights into the role of PF4, the most abundant protein released by activated platelets, on the development of atherosclerosis, delineate the pathways by which this occurs in vivo, and suggest potential methods to intervene in atherogenesis

描述（由申请人提供）：动脉粥样硬化是一种复杂的血管疾病，涉及炎症、凝血和脂质代谢之间的相互作用。越来越多的证据表明血小板活化在动脉粥样硬化病变的发生和/或扩展中起重要作用。由于血小板含有多种炎症、细胞粘附和内皮活化的调节剂，阐明血小板促进动脉粥样硬化形成的机制可能为干预提供新的机会。我的研究小组主要关注血小板特异性趋化因子血小板因子4（PF 4）在动脉粥样硬化中的作用。我们已经产生了初步的体内数据，支持PF 4是促动脉粥样硬化的概念。我们实验室以前的工作已经确定了两种可能导致PF 4致动脉粥样硬化性的受体依赖性途径。首先，PF 4抑制低密度脂蛋白受体（LDLR）依赖的低密度脂蛋白（LDL）降解。这导致LDL保留在细胞表面上，其易于修饰成氧化LDL（ox-LDL）。其次，PF 4通过LDL受体相关蛋白（LRP）激活NF-κ B（动脉粥样硬化和炎症相关的转录因子）。该提议的主要假设是PF 4激活这些途径中的一个或两个以促进动脉粥样硬化病变形成。我们进一步证实，PF 4四聚体在细胞表面糖胺聚糖（GAG）的存在下寡聚化，然后激活LDLR和/或LRP途径。为了验证这一假设，我们将研究PF 4在体内对动脉粥样硬化的作用，并通过三个相关的特定目标，使用体外模型系统阐明其在体内和血管细胞上的作用机制：SA I：“有助于促动脉粥样硬化的PF 4的结构特征”将进一步剖析体外这些途径的细节，重点是PF 4的结构特征。SA II：“描述PF 4对apoE-/-小鼠脂蛋白代谢和动脉粥样硬化的影响”将扩展我们对缺乏PF 4的apoE-/-小鼠的描述，并了解PF 4过表达在apoE-/-小鼠中的意义。SA III：“PF 4体内致动脉粥样硬化的机制”将研究LDLR和LRP途径对PF 4介导的动脉粥样硬化的重要性。这些研究将提供新的见解PF 4的作用，最丰富的蛋白质释放的活化血小板，动脉粥样硬化的发展，描绘的途径，这发生在体内，并提出潜在的方法来干预动脉粥样硬化的形成