Mechanisms of Platelet Activity in Vascular Disease

血管疾病中血小板活性的机制

• 批准号: 10551283
• 负责人: Jeffrey S Berger
• 金额: $ 101.7万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551283
• 关键词: Abdominal Aortic Aneurysm; Amputation; Animal Model; Area; Aspirin; Blood Platelets; Blood Vessels; Candidate Disease Gene; Cardiac; Cardiovascular system; Carotid Stenosis; Clinical; Code; Collection; Complex; Coronary Arteriosclerosis; Data; Disease; Effectiveness; Effector Cell; Event; Fostering; Functional disorder; Goals; Heart; Incidence; Inflammation; International; Knock-in; Knock-out; Leukocytes; Life; Limb structure; Lower Extremity; Medical; Megakaryocytes; Molecular; Morbidity - disease rate; Myocardial Infarction; Pathogenesis; Patients; Peripheral arterial disease; Persons; Phenotype; Platelet aggregation; Play; Positioning Attribute; Post-Transcriptional Regulation; Prevention; Procedures; Process; Property; Regulation; Research Design; Role; Sampling; Severities; Societies; Therapeutic; Transcript; United States; Untranslated RNA; Vascular Diseases; Work; advanced system; clinical biomarkers; cohort; cost; design; diagnostic strategy; follow-up; insight; monocyte; mortality; new therapeutic target; novel; platelet phenotype; prevent; prognostic; therapeutic target; transcriptome

PROJECT SUMMARY/ABSTRACT An estimated 15–20 million people in the United States have peripheral artery disease (PAD). Despite advances in medical therapy, PAD remains associated with considerable cardiac and limb morbidity and mortality. Currently, more invasive procedures are performed in the lower extremities than in the heart, demonstrating increasing costs to the system of advanced PAD. Although the pathogenesis of coronary artery disease (CAD) is well characterized, the pathophysiology of PAD is less understood and the mechanism(s) that regulate this complex disorder remain uncertain. While antiplatelet therapy (as a class effect) decreases the incidence and complications from PAD, we noted that the effectiveness of antiplatelet therapy differs between PAD and other vascular phenotypes. In contrast to CAD, aspirin was not particularly effective in PAD nor was there clinical benefit with more potent P2Y12 inhibition. Clearly, new directions are needed to better understand the role of platelets in PAD pathogenesis and identify new therapeutic targets. Our group demonstrated the importance in coding and noncoding RNAs in regulating platelet activity. Leveraging our established cohort of PAD patients with well-phenotyped platelet activities, we demonstrated the importance of platelet–leukocyte interactions (in contrast to platelet–platelet aggregation) in the pathogenesis of PAD. Moreover, we identified an aberrant post-transcriptional regulation of platelets in PAD and demonstrated that platelets play a central effector role in activating monocytes and fostering inflammation in PAD. Here, we propose to comprehensively investigate the relationship between (1) platelet activity, (2) the platelet transcriptome, and (3) effector cell properties in patients with PAD. We will analyze stored platelet samples from >1,000 patients with longitudinal follow-up, many of whom provided serial collections. Leveraging these valuable platelet samples, we will focus on identifying novel platelet transcripts associated with vascular phenotypes and incident cardiovascular events. For example, we will compare patients with (1) PAD vs. other vascular phenotypes (e.g., CAD, carotid artery stenosis, abdominal aortic aneurysm), (2) stable PAD vs. CLI, and (3) incident cardiac (myocardial infarction) vs. limb (major amputation) events. Mechanistic studies using both cultured megakaryocytes and animal models with platelet-specific knock-in and knock-out of candidate genes will characterize how these processes are regulated. We are also well positioned to validate our findings in well-established local, national, and international cohorts. Our data suggest these types of studies can provide conceptual advances in our understanding of the mechanisms influencing the pathogenesis and severity of PAD. These insights could be leveraged to design clinical biomarkers and therapeutic strategies to treat and prevent vascular disease and its life-threatening complications.

项目摘要/摘要 美国估计有1,50万人患有外围动脉疾病（PAD）。尽管 医疗疗法的进步，PAD仍然与心脏和肢体发病率以及 死亡。目前，下肢在下肢进行更多的侵入性程序， 证明了高级垫系统的成本增加。虽然冠状动脉的发病机理 疾病（CAD）的特征是，PAD的病理生理学知之甚少，机制 调节这种复杂疾病仍然不确定。而抗血小板疗法（作为班级效应）下降 垫的事件和并发症，我们注意到抗血小板治疗的有效性不同 在PAD和其他血管表型之间。与CAD相反，阿司匹林在PAD中不是特别有效 没有更多潜在的P2Y12抑制作用，也没有临床益处。显然，需要新的方向以更好 了解血小板在PAD发病机理中的作用并确定新的治疗靶标。我们的小组 证明了调节血小板活性中编码和非编码RNA的重要性。利用我们的 已建立的PAD患者队列具有良好的血小板活动，我们证明了 PAD发病机理中的血小板 - 白细胞相互作用（与血小板 - 血小板聚集）。 此外，我们确定了PAD中血小板的异常转录后调节，并证明了这一点 血小板在激活单核细胞和培养垫中的注射中起着中心效应子的作用。在这里，我们 建议全面研究（1）血小板活动之间的关系，（2）血小板 转录组和（3）PAD患者的效应细胞性质。我们将分析存储的血小板样品 纵向随访的1,000例患者，其中许多人提供了系列收集。利用这些 价值血小板样品，我们将专注于识别与血管相关的新型血小板转录本 表型和事件心血管事件。例如，我们将比较（1）PAD与其他患者 血管表型（例如CAD，颈动脉狭窄，腹主动脉瘤），（2）稳定的垫子与CLI， （3）事件心脏（心肌梗塞）与肢体（主要截肢）事件。机械研究使用 具有血小板特异性敲入和候选者的培养的巨核细胞和动物模型 基因将表征这些过程的调节方式。我们也很适合验证我们的发现 在建立良好的本地，国家和国际队列中。我们的数据表明这些类型的研究可以 在我们对影响发病机理的机制的理解中提供概念进步 垫的严重程度。这些见解可以利用来设计临床生物标志物和治疗策略 治疗和预防血管疾病及其威胁生命的并发症。