PLATELET-ACTIVATING FACTOR IN THROMBOTIC PLATELET-LEUKOCYTE INTERACTIONS

血栓性血小板-白细胞相互作用中的血小板激活因子

• 批准号: 7799803
• 负责人: THOMAS MCINTYRE
• 金额: $ 40.21万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7799803
• 关键词: Abbreviations; Acetyltransferase; Acute; Adhesions; Agonist; Animal Model; Antibodies; Antiphospholipid Antibodies; Aspirin; Blood Platelets; CD14 Antigen; Cells; Clinic; Clinical; Coronary; Disease; Endotoxins; Enzymes; Event; GTP-Binding Proteins; Genetic; Genetic Variation; Human; Immune system; Individual; Inflammation Mediators; Inflammatory; Integrins; Ischemia; Knowledge; Lead; Lecithin; Left; Leukocytes; Ligands; Link; Lipids; Lipopolysaccharides; Lipoproteins; Lysophosphatidylcholines; Mediator of activation protein; Myocardial; Organ; Pathway interactions; Phospholipids; Platelet Activating Factor; Predisposition; Process; Production; Prostaglandin Production; Prostaglandin-Endoperoxide Synthase; Proteins; Reaction; Receptor Activation; Reperfusion Injury; Reperfusion Therapy; Research Personnel; Role; Route; Sepsis; Signal Transduction; Source; Stents; Surface; System; TLR4 gene; Techniques; Testing; Thromboplastin; Thrombosis; Thromboxane A2; Thromboxane Production; Thromboxanes; Thrombus; Time; Tissues; Translating; Vasoconstrictor Agents; cyclooxygenase 2; cytokine; design; eicosanoid metabolism; endotoxin receptor; hemodynamics; in vivo; inhibitor/antagonist; leukocyte activation; lipid mediator; lung injury; novel; platelet activating factor receptor; programs; receptor; receptor function; success; synthetic enzyme

The phospholipid Platelet-activating factor (PAF) is perhaps the most powerful pro-inflammatory and prothromobtic lipid mediator yet defined. All cellular components of the acute inflammatory system express the single known receptor for PAF. PAF is synthesized by, and retained on the surface of, activated endothelial ceils where it stimulates tethered leukocytes. PAF accumulation normally is tightly controlled, but PAF has a role in thrombosis, sepsis and reperfusion damage. There are deficits in our knowledge of how, when, and where PAF receptor ligands are formed, how PAF is presented to cells of the innate immune system and how PAF stimulated cells interact with other cells. We do not know whether PAF receptor ligands are formed during stent placement, whether PAF stimulated leukocytes provide platelets with substrate for thromboxane production even when platelet cyclooxygenase has been inhibited by aspirin, and we do not know whether PAF production by leukocytes stimulated with endotoxin is mimicked by endogenous agonists that include anti-phospholipid antibodies. We propose to identify the pathways leading to activation of the rate-limiting PAF synthetic activity, determine whether individuals vary in their ability to make PAF, take advantage of new information and techniques to purify the enzyme responsible for PAF synthesis for eventual rational inhibitor design, and identify and modulate mechanisms that cause microparticle formation and PAF release, and to determine whether these parameters correlate with thrombosis. We will define the pro-thrombotic lipids released during stent placement, we will investigate alternate routes to generate thromboxane Aa, and determine whether this correlates with susceptibility to slow reflow after stent placement, and we will test alternate, endogenous ligands of TLR4 as leukocyte agonists. We have four aims: Aim 1. Mechanistically define adhesion-dependent PAF synthesis in PMN. Aim 2. Purify and molecularly characterize the leukocyte PAF acetyltransferase synthetic enzyme. Aim 3. Identify factors that extend the effect of PAF through microparticle release. Aim 4. Define novel routes to leukocyte activation and inflammatory mediator production

磷脂血小板激活因子(PAF)可能是最有效的促炎和促凝血药 脂类介体尚未定义。急性炎症系统的所有细胞成分都表达 PAF的单一已知受体。PAF是由活化的内皮细胞合成并保留在其表面的 刺激系留的白细胞的细胞。PAF的积累通常是严格控制的，但PAF有一个 在血栓形成、败血症和再灌注损伤中的作用。 我们对PAF受体配体是如何、何时、在哪里形成的，PAF是如何形成的，我们的认识是不足的 呈现给先天免疫系统的细胞，以及PAF刺激的细胞如何与其他细胞相互作用。我们 不知道支架置入过程中是否形成PAF受体配体，是否刺激PAF 白细胞为血小板提供产生血栓素的底物，即使当血小板环氧合酶 已经被阿司匹林抑制，我们不知道在阿司匹林刺激下的白细胞是否产生PAF 内毒素被包括抗磷脂抗体在内的内源性激动剂模仿。 我们建议确定导致限速PAF合成活性激活的途径， 确定个人制作PAF的能力是否不同，利用新信息和 纯化负责PAF合成的酶以进行最终合理的抑制剂设计的技术，以及 确定和调节导致微粒形成和PAF释放的机制，并确定 这些参数是否与血栓形成相关。我们将定义在治疗过程中释放的促血栓形成脂质 支架置入后，我们将研究产生血栓素AA的替代途径，并确定这是否 与支架置入后缓慢复流的易感性相关，我们将测试替代、内源性 作为白细胞激动剂的TLR4的配体。我们有四个目标： 目的1.从力学角度定义PMN中黏附依赖性PAF的合成。 目的2.分离纯化白细胞PAF乙酰转移酶合成酶，并对其进行分子鉴定。 目的3.确定通过微粒释放延长PAF作用的因素。 目的4.确定白细胞激活和炎症介质产生的新途径