Overall Summary/Abstract This Outstanding Investigator Award R35 program addresses previously-unexplored mechanisms by which regulation of gene expression at the translational level controls the functions of megakaryocytes and platelets, in the setting of health and disease. Studies will employ basic and clinical investigations in humans and mice to comprehensively determine how translational pathways that converge on Eukaryotic Initiation Factor 4E (eIF4E) regulate megakaryocyte and platelet biology. Roles for translational control pathways in megakaryocytes have not previously been studied, their functional significance in circulating platelets is uncertain, and it is unknown how disease situations alter translational responses of megakaryocytes and platelets. Thus, successful completion of the research objectives will fill key gaps in knowledge that need to be addressed in heart, lung, and blood research. Results generated will also determine if translational control pathway inhibitors, which are currently being tested in the clinic, have off-target effects on megakaryocytes and platelets.