MRP-14 and Cardiovascular Disease

MRP-14 与心血管疾病

基本信息

批准号：
7881670
负责人：
Daniel I Simon
金额：
$ 38.88万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
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/7881670
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 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 Plasma Play Protein Biosynthesis Proteins Recurrence Regulation Reperfusion Therapy Research Personnel Risk Risk Factors Role Rupture S100A9 gene Signal Transduction Thrombosis Thromboxanes Thrombus Transcript Vascular Diseases Woman Women&apos s Health acute coronary syndrome aged artery occlusion atherogenesis base case control cohort cytokine 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

项目摘要

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）：急性心肌梗死（AMI）通常由动脉粥样硬化斑块破裂和血栓形成引起。血小板构成此类血栓的主要成分，但 AMI 发生前的精确分子事件仍不确定。转录分析可以产生公正的、机制性疾病的见解。然而，AMI 后的基因表达可能反映斑块破裂和血栓形成的触发事件或下游后果。血小板由巨核细胞的细胞质延伸产生，保留了巨核细胞衍生的 mRNA。由于血小板是无核的，因此血小板转录组反映了巨核细胞衍生的 mRNA。因此，血小板的转录谱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。我们对急性 ST 段抬高型心肌梗死 (STEMI) 或稳定型冠状动脉疾病 (CAD) 患者的血小板 mRNA 进行了分析。从 STEMI 和 CAD 患者中分离的血小板含有 54 个差异表达的转录本。微阵列中 STEMI 最强的鉴别因子之一是骨髓相关蛋白 14 (MRP-14) (P=0.002)。 MRP-14 是 Ca2+ 调节蛋白 S100 家族的成员，可调节钙信号传导、细胞骨架重组和白细胞运输。 STEMI 患者血浆 MRP-8/14 异二聚体水平较高（P<0.001）。在一项针对表面健康女性的前瞻性巢式病例对照研究中，首次心血管 (CV) 事件的风险随着 MRP-8/14 每增加四分位数而增加，因此水平最高的女性发生首次心血管 (CV) 事件的风险增加 4 倍任何 CV 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 MRP-8/14 蛋白存在于血小板中，MRP-14 的缺乏会减少血小板介导的血栓形成。这些发现是修订后的转化应用的基础。该提案的中心假设是，MRP-14 在血管损伤和血栓形成中调节血小板和白细胞功能，并且 MRP-8/14 的血浆水平可作为 CV 事件的有用预测因子。该提案的总体目标是确定 MRP-14 在 CV 疾病中的作用。我们的具体目标是：（1）检测MRP-14是否在体外调节血小板和白细胞功能； (2) 利用野生型和MRP-14缺陷型小鼠研究MRP-14在血管损伤和血栓形成中的作用； (3) 使用 PROVE IT-TIMI-22 的前瞻性、巢式病例对照研究来确定 MRP-8/14 是否可以预测急性冠脉综合征患者复发 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为开发预测和治疗动脉粥样硬化血栓事件的新策略提供必要的见解。