MRP-14 and Cardiovascular Disease

MRP-14 与心血管疾病

• 批准号: 7487781
• 负责人: Daniel I Simon
• 金额: $ 39.07万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487781
• 关键词: Acids; Acute; Acute myocardial infarction; Affect; Angioplasty; Arterial Fatty Streak; Atherosclerosis; Biological; Blood Platelets; Blood Vessels; Bone Marrow; Breeding; C-reactive protein; Calcium; Calcium Signaling; Calgranulin B; Cardiac Catheterization Procedures; Cardiovascular Diseases; Cardiovascular system; Carotid Artery Thrombosis; Cell Proliferation; Cell physiology; Chest Pain; Clinical; Complex; Convalescence; Coronary; Coronary Arteriosclerosis; Cytoskeletal Modeling; Data; Diet; Disease; Disruption; Elevation; Enrollment; Etiology; Event; Family; Future; Gene Expression; Gene Expression Profile; Generations; Genetic Transcription; In Vitro; Individual; Inflammation; Inflammatory; Injury; Integrins; Laboratories; Lasers; Lesion; Leukocyte Trafficking; Leukocytes; Low Density Lipoprotein Receptor; Mediating; Megakaryocytes; Messenger RNA; Metabolism; Microcirculation; Modeling; Molecular; Mus; Myelogenous; Myocardial Infarction; Nested Case-Control Study; Odds Ratio; Patients; Physiological reperfusion; Plasma; Play; Protein Biosynthesis; Proteins; Recurrence; Regulation; Reperfusion Therapy; Research Personnel; Risk; Risk Factors; Role; Rupture; S100A9 gene; Signal Transduction; Standards of Weights and Measures; Thrombosis; Thromboxanes; Thrombus; Transcript; Vascular Diseases; Woman; Women' s Health; acute coronary syndrome; aged; artery occlusion; atherogenesis; base; case control; cohort; cysteine rich protein; cytokine; day; extracellular; factor C; femoral artery; in vivo; indexing; insight; intravital microscopy; member; neointima formation; novel; novel strategies; programs; prospective; research study; response; trend; vascular inflammation

DESCRIPTION (provided by applicant): Acute myocardial infarction (AMI) commonly results from atherosclerotic plaque disruption and thrombosis. Platelets constitute a major component of such thrombi, yet the precise molecular events that immediately precede AMI remain uncertain. Transcriptional profiling can yield unbiased, mechanistic disease insights. However, gene expression following AMI may reflect either triggering events or downstream consequences of plaque rupture and thrombosis. Generated from cytoplasmic extensions from megakaryocytes, platelets retain megakaryocyte-derived mRNAs. Since platelets are anuclear, the platelet transcriptome mirrors megakaryocyte-derived mRNAs. Thus, transcriptional profiling of platelets provides a novel window on gene expression preceding acute coronary events. We profiled platelet mRNA from patients with acute ST-segment elevation myocardial infarction (STEMI) or stable coronary artery disease (CAD). Platelets isolated from STEMI and CAD patients contained 54 transcripts that were differentially expressed. One of the strongest discriminators of STEMI in the micorarrays was myeloid-related protein-14 (MRP-14) (P=0.002). MRP-14 is a member of the S100-family of Ca2+modulated proteins that modulate calcium signaling, cytoskeletal reorganization, and leukocyte trafficking. Plasma levels of MRP-8/14 heterodimer were higher in STEMI patients (P<0.001). In a prospective, nested case-control study among apparently healthy women, the risk of a first cardiovascular (CV) event increased with each increasing quartile of MRP-8/14 such that women with the highest levels had a 4-fold increase risk of any CV event (P<0.001). Risks were independent of standard risk factors and CRP. Furthermore, preliminary data indicate that MRP-8/14 protein is present in platelets and deficiency of MRP-14 reduces platelet-mediated thrombosis. These findings are the basis for this revised translational application. The central hypotheses of this proposal are that MRP-14 modulates platelet and leukocyte functions in vascular injury and thrombosis and that plasma level of MRP-8/14 serves as a useful predictor of CV events. The overall objective of this proposal is to define the role of MRP-14 in CV disease. Our specific aims are: (1) To examine whether MRP-14 modulates platelet and leukocyte functions in vitro; (2) To investigate the role of MRP-14 in vascular injury and thrombosis using wild-type and MRP-14-deficient mice; and (3) To determine whether MRP-8/14 predicts the risk of recurrent CV events in patients presenting with acute coronary syndromes using a prospective, nested case-control study from PROVE IT-TIMI-22. The experiments outlined in this proposal should clarify the role of MRP-14 in vascular injury and thrombosis. Because inflammation plays a critical role in atherosclerosis, understanding the molecular and cellular mechanisms of vascular inflammation will provide insights necessary to develop novel strategies for predicting and treating atherothrombotic events.

描述（由申请人提供）：急性心肌梗塞（AMI）通常是由于动脉粥样硬化斑块的破坏和血栓形成而引起的。血小板构成了这种血栓的主要组成部分，但是在AMI之前的精确分子事件仍然不确定。转录分析可以产生公正的机械疾病见解。但是，AMI之后的基因表达可能反映了触发事件或斑块破裂和血栓形成的下游后果。血小板由巨核细胞的细胞质扩展产生，保留巨核细胞衍生的mRNA。由于血小板是动态的，因此血小板转录组反映了巨核细胞衍生的mRNA。因此，血小板的转录分析为急性冠状动脉事件之前的基因表达提供了一个新的窗口。我们从急性ST段升高心肌梗塞（STEMI）或稳定的冠状动脉疾病（CAD）的患者中介绍了血小板mRNA。从STEMI和CAD患者中分离出的血小板包含54个差异表达的转录本。在割阵中，STEMI最强的歧视剂之一是髓样相关的蛋白质14（MRP-14）（P = 0.002）。 MRP-14是调节钙信号传导，细胞骨架重组和白细胞运输的Ca2+调制蛋白S100家庭的成员。 STEMI患者的MRP-8/14异二聚体的血浆水平较高（P <0.001）。在一项前瞻性的，嵌套的病例对照研究中，在明显健康的女性中，随着MRP-8/14的每一个四分位数的增加，首次心血管（CV）事件的风险增加任何简历事件（p <0.001）。风险独立于标准风险因素和CRP。此外，初步数据表明，血小板中存在MRP-8/14蛋白，MRP-14的缺乏降低了血小板介导的血栓形成。这些发现是此修订的翻译应用的基础。该提案的中心假设是MRP-14调节血小板和白细胞在血管损伤和血栓形成中的功能，以及MRP-8/14的血浆水平是CV事件的有用预测指标。该提案的总体目的是定义MRP-14在CV疾病中的作用。我们的具体目的是：（1）检查MRP-14是否在体外调节血小板和白细胞功能； （2）研究MRP-14在使用野生型和MRP-14缺陷型小鼠的血管损伤和血栓形成中的作用； （3）确定MRP-8/14是否预测了使用Prove IT-Timi-22的前瞻性，嵌套的病例对照研究来预测患有急性冠状动脉综合征的患者复发性CV事件的风险。该提案中概述的实验应阐明MRP-14在血管损伤和血栓形成中的作用。由于炎症在动脉粥样硬化中起着至关重要的作用，因此了解血管炎症的分子和细胞机制将提供必要的见解，以开发预测和治疗动脉粥样硬化事件的新型策略。