Pathway maps of platelet phenotype and function

项目摘要 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。朴槿惠也坚持 功能障碍的内皮细胞，在那里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发展血管炎症， 包括动脉粥样硬化。正在进行的旨在了解和靶向疾病特异性血小板活性的努力 已经表征了一系列与炎症、血栓形成和血栓形成相关的血小板功能表型， 其他条件。尽管发现了关键的分子改变，突出了这些差异， 表型，目前仍不清楚不同的血小板表型如何发展，它们应该如何定义， 最后，如何定位。我们假设血小板止血，炎症和其他 表型由细胞内信号传导途径和效应物的系统活化决定， 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 定义进展血小板粘附（Aim 1）、分泌（Aim 2）和聚集的细胞内信号传导事件 (Aim 3）止血程序，并确定这些反应如何在机械上不同的背景下， 血管炎症我们将通过使用高通量的，基于蛋白质组学的 测量和绘制血小板功能相关的细胞内信号事件和途径的工作流程 具体的实验和生理背景。我们现在使用这套蛋白质组学，计算和细胞 生物学工具，以建立途径地图细胞内信号转导关系的血小板活化程序。在这 建议，我们使用这种一流的途径映射方法与其他生理和 系统生物学工具，以解决血小板信号程序如何指定血小板表型， 止血和炎症反应。最终，这项工作将产生知识，以及一个概念 旨在定义和理解血小板在止血以及 炎症和疾病的表现。

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.