Plasma F11R and Cardiovascular Outcomes in Patients with Coronary Artery Disease

冠状动脉疾病患者的血浆 F11R 和心血管结果

• 批准号: 7770927
• 负责人: Erdal Cavusoglu
• 金额: $ 23.76万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7770927
• 关键词: Accounting; Acute; Adhesions; Adhesiveness; Animal Model; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Basic Science; Biological Markers; Blood Platelets; Cardiac; Cardiovascular system; Cell Adhesion Molecules; Chronic; Clinical Data; Clinical Research; Clinical Trials; Coronary Angiography; Coronary Arteriosclerosis; Data Reporting; Databases; Detection; Development; Disease; Early Diagnosis; Endothelial Cells; Endothelium; Enzyme-Linked Immunosorbent Assay; Event; Genes; Hospitals; Human; Human Cloning; Immunoglobulins; Inflammation; Inflammatory; Institution; Investigation; Knockout Mice; Laboratories; Lead; Link; Measures; Medical center; Messenger RNA; Methods; Mus; Myocardial Infarction; Orthologous Gene; Outcome; Pathogenesis; Patients; Peripheral Vascular Diseases; Plasma; Play; Proteins; Reporting; Research; Risk; Role; Serum; Severities; Stratification; Stroke; Surface; Thrombosis; Thrombus; Time; United States Department of Veterans Affairs; Unstable angina; Vascular Diseases; Work; atherogenesis; base; cardiovascular risk factor; cohort; cytokine; junctional adhesion molecule; member; mortality; novel; novel therapeutics; percutaneous coronary intervention; prognostic; prospective; public health relevance; receptor; receptor expression

DESCRIPTION (provided by applicant): There is a growing body of evidence showing that the interaction between platelets and endothelial cells contributes significantly to the pathogenesis of atherosclerosis. Platelet adhesion to the inflamed endothelium triggers the formation of thrombi leading to atherosclerotic lesions. Furthermore, platelets are known to play a critical role in the acute exacerbations of chronic atherosclerotic disease, such as unstable angina and myocardial infarction, as well as in the thrombotic complications of percutaneous coronary intervention. A key molecule identified recently as critical for platelet adhesion to a thrombogenic endothelial surface is the F11 receptor (F11R). F11R is a novel cell adhesion molecule, a member of the immunoglobulin superfamily, and a human ortholog of a murine cell adhesion molecule found in endothelial cells termed Junctional Adhesion Molecule (JAM). It has been demonstrated that F11R plays a critical role in the adhesion of platelets to cytokine-inflamed endothelial cells, accounting for approximately 40% of this adhesiveness in normal controls. In addition, studies conducted at the applicant's institution have shown that F11R expression is increased in atherosclerotic plaques in an animal model of atherosclerosis, the apoE knock-out mouse. The human gene for F11R has recently been identified, sequenced and cloned. Furthermore, our laboratory has recently developed a sensitive ELISA to measure levels of soluble F11R in the plasma or sera of patients. Using this novel ELISA, we have shown that plasma F11R is independently associated with the presence and severity of angiographically- defined coronary artery disease. The objectives of this proposal are to examine the hypotheses that 1) the baseline plasma levels of F11R in patients with known or suspected CAD referred for coronary angiography are independent predictors of the development of long-term adverse cardiovascular outcomes, and 2) the baseline plasma levels of F11R in patients undergoing percutaneous coronary intervention are independent predictors of both short- and intermediate-term outcomes. The project, which is based on recent findings in basic science research, represents the first clinical investigation of F11R as a prognostic biomarker in patients with coronary artery disease. PUBLIC HEALTH RELEVANCE: This proposal will expand our preliminary work demonstrating a critical role for F11R in atherosclerosis and inflammatory thrombosis. The current proposal represents the first study in humans to examine the prognostic significance of baseline plasma F11R levels in patients with known or suspected coronary artery disease. It is expected that this work will contribute substantially to the biomarker field and lead to improvements in methods of cardiovascular risk stratification.

描述(由申请人提供)：越来越多的证据表明，血小板和内皮细胞之间的相互作用在动脉粥样硬化的发病机制中起着重要作用。血小板与炎症的内皮细胞黏附会触发血栓的形成，从而导致动脉粥样硬化病变。此外，众所周知，血小板在慢性动脉粥样硬化性疾病的急性加重中起关键作用，如不稳定心绞痛和心肌梗死，以及经皮冠状动脉介入治疗的血栓并发症。最近发现的一个关键分子是F11受体(F11R)，它是血小板与血栓形成的内皮细胞表面黏附的关键分子。F11R是一种新的细胞黏附分子，是免疫球蛋白超家族的成员，也是内皮细胞中发现的一种被称为连接黏附分子(JAM)的小鼠细胞黏附分子的人类同源基因。已经证明，F11R在血小板与细胞因子炎症的内皮细胞的黏附中起关键作用，在正常对照组中约占这种黏附的40%。此外，在申请人所在机构进行的研究表明，在动脉粥样硬化的动物模型apoE基因敲除小鼠的动脉粥样硬化斑块中，F11R的表达增加。人类F11R基因最近被鉴定、测序和克隆。此外，我们的实验室最近开发了一种灵敏的ELISA方法来检测患者血浆或血清中可溶性F11R的水平。使用这种新型的酶联免疫吸附试验，我们已经证明血浆F11R与冠状动脉造影术定义的冠状动脉疾病的存在和严重程度独立相关。这项建议的目的是检验以下假设：1)经冠状动脉造影术检查的已知或疑似冠心病患者的基线血浆F11R水平是发展为长期不良心血管结果的独立预测因素，以及2)接受经皮冠状动脉介入治疗的患者的基线血浆F11R水平是短期和中期结果的独立预测因素。该项目基于基础科学研究的最新发现，代表了F11R作为冠状动脉疾病患者预后生物标志物的首次临床研究。 公共卫生相关性：这项提案将扩大我们的前期工作，展示F11R在动脉粥样硬化和炎症性血栓形成中的关键作用。目前的建议是第一项在人类中研究基线血浆F11R水平对已知或可疑冠状动脉疾病患者预后意义的研究。预计这项工作将对生物标记物领域做出实质性贡献，并导致心血管风险分层方法的改进。