Pathway maps of platelet phenotype and function

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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.