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.

项目概要/摘要 据估计，美国有 15-2000 万人患有外周动脉疾病 (PAD)。 随着医学治疗的进步，外周动脉疾病 (PAD) 仍然与相当大的心脏和肢体发病率相关， 目前，在下肢进行的侵入性手术比在心脏进行的手术更多。 尽管冠状动脉的发病机制表明晚期 PAD 系统的成本不断增加。 疾病 (CAD) 已得到很好的表征，但对 PAD 的病理生理学了解较少，其机制 调节这种复杂疾病的机制仍不确定，而抗血小板治疗（作为一种类别效应）会减少。 PAD 的发病率和并发症，我们注意到抗血小板治疗的有效性不同 PAD 与其他血管表型之间的比较 与 CAD 相比，阿司匹林对 PAD 并不是特别有效。 更有效的 P2Y12 抑制也没有临床益处，显然，需要新的方向来更好地进行治疗。 了解血小板在 PAD 发病机制中的作用并确定新的治疗靶点。 编码和非编码 RNA 在调节血小板活性方面的重要性。 我们建立了具有良好表型血小板活性的 PAD 患者队列，证明了 PAD 发病机制中的血小板 - 白细胞相互作用（与血小板 - 血小板聚集相反）。 此外，我们还发现了 PAD 中血小板的异常转录后调节，并证明 血小板在激活单核细胞和促进外周动脉疾病 (PAD) 炎症中发挥着核心效应作用。 建议全面研究（1）血小板活性，（2）血小板 转录组，以及 (3) PAD 患者的效应细胞特性 我们将分析储存的血小板样本。 来自超过 1,000 名进行纵向随访的患者，其中许多人提供了连续收集的数据。 有价值的血小板样本，我们将专注于识别与血管相关的新型血小板转录本 例如，我们将比较患有 (1) PAD 的患者与其他患者。 血管表型（例如 CAD、颈动脉狭窄、腹主动脉瘤），(2) 稳定 PAD 与 CLI， (3) 心脏（心肌梗死）事件与肢体（大截肢）事件的机制研究。 培养的巨核细胞和动物模型均具有候选血小板特异性敲入和敲除 基因将描述这些过程的调节方式，我们也有能力验证我们的发现。 我们的数据表明，这些类型的研究可以。 为我们理解影响发病机制的机制提供了概念上的进展 这些见解可用于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危及生命的并发症。