Platelet Exocytosis and Endocytosis in Thrombosis and Immunity

Platelets are critical for systemic vascular health. As the most abundant responsive “cells” in circulation, they serve as sentries detecting vascular damage and circulating pathogens. Despite advances in understanding signaling from vascular damage detection, our view of how activated platelets execute the steps needed for clot formation is limited. Over the past 2+ decades we have probed the mechanisms of platelet secretion and how it affects hemostasis. Using genetically altered models, we determined that modulating secretion allows for control of thrombus growth without compromising hemostasis. Building on that advance, a better understanding of platelet exocytosis is clearly needed to more logically develop therapeutic strategies. Increasingly, platelets are also being associated with immune responses, yet the mechanisms underlying these non-hemostatic functions are largely unknown. We posit that endocytosis is important for these platelet functions. Our work on exocytosis led to a greater appreciation of platelet endocytosis and endo-lysomal trafficking and processing of endocytosed cargo. We discovered that uptake of pathogens, such as viruses, activates platelets and thus could be the underlying cause of the increased ischemic thrombosis seen in chronically infected AIDS/HIV patients. However, very little is known about platelet endocytosis and next to nothing is known about how platelets traffic and process endocytosed material. Our research program seeks to fill these gaps in knowledge. Building on our innovative past work (>50 publications), we will further define platelet membrane trafficking (endocytosis, exocytosis, cargo sorting/processing, etc.) and define how it contributes to platelet function. We hypothesize that these trafficking processes, endo- and exocytosis, are essential for platelet-specific functions. To address this hypothesis, we will examine platelet exocytosis and endocytosis at mechanistic and physiological levels. Our group has developed an extensive suite of reagents, transgenic mouse strains, and technologies with which to study the basic aspects of platelet “cell biology”. Going forward, we will use these powerful tools and approaches to further define how platelet membrane trafficking (exo- and endocytosis) affects hemostasis/thrombosis and immune responses at molecular and organismal levels. The data generated will have direct applications to the understanding and treatment of human disease, especially thrombotic diseases which accounts for 1/4 deaths world-wide and chronic viremia, e.g., AIDS/HIV1, which increases CVD risk by more than two-fold.