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: 7493848
• 负责人: THOMAS MCINTYRE
• 金额: $ 38.39万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7493848
• 关键词: Abbreviations; Acetyltransferase; Acute; Adhesions; Agonist; Animal Model; Antibodies; Antiphospholipid Antibodies; Aspirin; Blood Platelets; Cells; Clinic; Clinical; Condition; Coronary; Disease; Endotoxins; Enzymes; Event; GTP-Binding Proteins; Genetic Variation; Human; Immune system; Individual; Inflammatory; Integrins; Ischemia; Knowledge; Lead; Lecithin; Left; Leukocytes; Ligands; Link; Lipids; Lipopolysaccharides; Lipoproteins; Localized; Lysophosphatidylcholines; Mediator of activation protein; Myocardial; Organ; Pathway interactions; Phospholipids; Physiological reperfusion; Placement; Platelet Activating Factor; Predisposition; Process; Production; Prostaglandin Production; Prostaglandin-Endoperoxide Synthase; Proteins; Rate; 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 1; 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

磷脂血小板活化因子（PAF）可能是最强大的促炎和促血栓作用