Pathway maps of platelet phenotype and function

项目总结 作为止血的主要细胞介质，血小板被优化以通过快速止血限制出血 内皮损伤部位的黏附、分泌和聚集反应。血小板也会黏附于 功能障碍的内皮细胞，在那里它们分泌促炎分子并形成聚集物 白细胞以与慢性疾病的发病机制相关的方式促进血管炎症， 包括动脉粥样硬化。旨在了解和靶向疾病特有的血小板活性的持续努力 表征了一系列与炎症、血栓形成和 其他条件。尽管发现了关键的分子变化，突出了它们之间的差异 表型，尚不清楚不同的血小板表型是如何发展的，它们应该如何定义，以及， 归根结底，他们应该如何成为目标。我们假设血小板止血、发炎和其他 表型由细胞内信号通路和效应器的系统激活决定 产生特定的血小板功能输出，以响应生理环境。我们的目标是系统地 确定促进血小板黏附(目标1)、分泌(目标2)和聚集的细胞内信号事件 (目标3)在止血方案中，并确定这些反应在以下背景下如何机械地不同 血管发炎。我们将通过使用高通量、基于蛋白质组学的 测量和绘制细胞内信号事件和潜在的血小板功能途径的工作流程 具体的实验和生理环境。我们现在使用这套蛋白质组学，计算和细胞 构建途径的生物工具绘制了血小板激活程序中的细胞内信号关系图。在这 建议，我们使用这一一流的路径映射方法与其他生理和 系统生物学工具解决血小板信号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以及概念性的 定义和理解止血中血小板调节的系统水平机制的方法 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.