Abstract Number: PB1717
Meeting: ISTH 2020 Congress
Background: Current antiplatelet therapies focus mainly on inhibiting platelet activation. The cyclic adenosine monophosphate-protein kinase A signalling (cAMP-PKA) pathway is the main physiological route for platelet inhibition, yet many downstream mediators of PKA remain to be elucidated.
Aims: We aim to use a network biology approach to find molecular “switches” downstream of the cAMP-PKA pathway that are involved in the reversal of platelet activation.
Methods: We used a publicly available phosphoproteomics dataset to create a selection of proteins involved in the reversal of platelet activation. We selected proteins based on existing knowledge of platelet activation pathways. Proteins downstream of prostacyclin were included and proteins downstream of adenosine diphosphate were omitted from our selection. Using the STRING database, a protein-protein interaction network of the 30 selected proteins with potential involvement in platelet deactivation plus 20 additional relevant interaction partners was constructed. The likelihood of the proteins being phosphorylated by PKA was predicted using a Group-based prediction system (GPS 5.0) and visualized in the network. Moreover, the degree of phosphopeptide regulation following platelet deactivation by Iloprost, a stable prostacyclin analogue, was also visualized on the nodes.
Results: Using a comprehensive quantitative platelet proteome dataset, we were able to show that all original proteins and 60% of the additional proteins are present in human platelets under normal conditions. Furthermore, Gene Ontology analysis revealed enrichment of biological processes related to platelet activation, such as cytoskeletal reorganization and vesicle secretion, collectively confirming the validity of our network.
Conclusions: Our method describes a versatile approach to analyse large datasets in a coherent fashion. Currently, we are supplementing our network with existing pathway information from Reactome or WikiPathways. Additionally, enriching our network with drug interactions obtained from the DrugBank database can help us select the most promising targets to explore further in microfluidic models that mimic the vascular microenvironment.
To cite this abstract in AMA style:Lemmens TP, Coenen DM, Niessen ICL, Coort SLM, Koenen RR, Kutmon M, Cosemans JMEM. Finding the “Switch” in Platelet Activation – Prediction of Key Mediators Involved in the Reversal of Platelet Activation Using a Network Biology Approach [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/finding-the-switch-in-platelet-activation-prediction-of-key-mediators-involved-in-the-reversal-of-platelet-activation-using-a-network-biology-approach/. Accessed May 16, 2022.
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