Pathway Maps of Platelet Phenotype and Function

血小板表型和功能的通路图

• 批准号: 10038760
• 负责人: JOSEPH E ASLAN
• 金额: $ 16.6万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10038760
• 关键词: Address; Adhesions; Adhesives; Affect; Agonist; Alpha Granule; Atherosclerosis; Biochemical; Biological; Blood Cells; Blood Platelets; Cardiovascular Diseases; Cause of Death; Cell model; Cell-Cell Adhesion; Cells; Chronic Disease; Coagulation Process; Complement; Complex; Cues; Cytokine Receptors; Cytoplasmic Granules; Data Analyses; Disease; Endothelium; Event; Filopodia; Glycoproteins; Goals; Hemorrhage; Hemostatic Agents; Hemostatic function; Image; Inflammation; Inflammatory; Inflammatory Response; Injury; Integrins; Knowledge; Leukocytes; Maps; Measurement; Measures; Mediating; Mediator of activation protein; Methodology; Methods; Modeling; Molecular; Morbidity - disease rate; Output; P-Selectin; Pathogenesis; Pathway interactions; Phenotype; Phospholipase; Phosphorylation; Physiological; Platelet Activation; Process; Proteins; Proteomics; Public Health; Purinoceptor; Receptor Signaling; Regulation; Role; Signal Pathway; Signal Transduction; Site; Specific qualifier value; System; Systems Biology; Testing; Thrombosis; Work; adhesion receptor; base; disability; extracellular; improved; in vivo; mortality; novel; platelet function; platelet phenotype; prevent; programs; receptor; release factor; response; tool; trafficking; vascular inflammation

PROJECT SUMMARY As the primary cellular mediators of hemostasis, platelets are optimized to limit bleeding through rapid adhesion, secretion and aggregation responses at sites of endothelial injury. Platelets also adhere to dysfunctional endothelium, where they secrete proinflammatory molecules and form aggregates with leukocytes to progress vascular inflammation in a manner relevant to the pathogenesis of chronic diseases, including atherosclerosis. Ongoing efforts aiming to understand and target platelet activities specific to disease have characterized a spectrum of platelet functional phenotypes associated with inflammatory, thrombotic and other conditions. Despite the identification of key molecular alterations that highlight differences between these phenotypes, it remains unclear how different platelet phenotypes develop, how they should be defined, and, ultimately, how they should be targeted. We hypothesize that platelet hemostatic, inflammatory and other phenotypes are determined by the systematic activation of intracellular signaling pathways and effectors that result in specific platelet functional outputs in response to physiological context. We aim to systematically define intracellular signaling events that progress platelet adhesion (Aim 1), secretion (Aim 2) and aggregation (Aim 3) in hemostatic programs and to determine how these responses mechanistically differ in the context of vascular inflammation. We will engage these studies through the use of a high-throughput, proteomics-based workflow that measures and maps intracellular signaling events and pathways underlying platelet function in specific experimental and physiological contexts. We now use this set of proteomics, computational and cell biological tools to build pathway maps intracellular signaling relations in platelet activation programs. In this proposal, we use this first-in-class pathway mapping methodology together with other physiological and systems biology tools to address how platelet signaling programs specify platelet phenotypes favoring hemostatic and inflammatory responses. Ultimately, this work will generate knowledge as well as a conceptual means to define and understand systems level mechanisms of platelet regulation in hemostasis as well as in inflammation and the manifestation of disease.

项目概要 作为止血的主要细胞介质，血小板被优化以通过快速止血来限制出血。 内皮损伤部位的粘附、分泌和聚集反应。血小板也粘附在 功能失调的内皮，它们分泌促炎分子并与 白细胞以与慢性疾病发病机制相关的方式进展血管炎症， 包括动脉粥样硬化。正在进行的努力旨在了解和针对疾病特有的血小板活性 已经表征了与炎症、血栓形成和相关的一系列血小板功能表型 其他条件。尽管识别出关键的分子改变突出了这些之间的差异 表型，目前尚不清楚不同的血小板表型如何发展，如何定义它们，以及， 最终，他们应该如何定位。我们假设血小板具有止血、抗炎和其他作用 表型是由细胞内信号通路和效应器的系统激活决定的 导致响应生理环境的特定血小板功能输出。我们的目标是系统地 定义促进血小板粘附（目标 1）、分泌（目标 2）和聚集的细胞内信号传导事件 （目标 3）在止血程序中，并确定这些反应在机制上有何不同 血管炎症。我们将通过使用高通量、基于蛋白质组学的方法来开展这些研究 测量和绘制血小板功能背后的细胞内信号事件和通路的工作流程 特定的实验和生理背景。我们现在使用这套蛋白质组学、计算和细胞 构建血小板激活程序中细胞内信号传导关系通路图的生物工具。在这个 建议，我们将这种一流的路径图谱方法与其他生理学和 系统生物学工具可解决血小板信号传导程序如何指定有利于血小板表型的问题 止血和炎症反应。最终，这项工作将产生知识和概念 是指定义和理解止血和血小板调节的系统水平机制。 炎症和疾病的表现。