We are seeking to understand the molecular cell biology regulating how circulating blood platelets contribute to hemostasis, thrombosis, and immune response, and to apply this understanding to modulate platelet function in various contexts. Our research program spans molecular studies of control of platelet gene expression, the cell biological outcomes of this regulation, physiological studies of platelet function, and development of tools for pre-clinical applications in health and disease.
Platelet microRNAs as modulators of hemostasis and thrombosis
Hemostasis (prevention of blood leak after vascular injury by formation of a clot) and thrombosis (clot formation generally not in response to injury, which can cause pathological complications) are considered the primary functions of platelets, and platelets require protein products of many protein-coding genes to carry out these functions. In addition to those genes, platelets are enriched in small non-coding RNAs known as microRNAs (miRNAs) that are generally understood to function to dampen the expression levels of protein-coding genes, and thereby suppress gene activity. We have found that miRNAs are important regulators of platelet function. We are seeking to understand how miRNAs regulate platelet function in hemostasis and thrombosis, to identify the specific miRNAs and gene targets involved, and to develop strategies to manipulate miRNA function and modulate platelet reactivity to support hemostasis or suppress thrombotic potential.
Molecular control of mRNA translation in platelets
Platelets are anucleate cell fragments that circulate in blood for 7-10 days. Hence, platelets lack genomic DNA but they do contain protein-coding message RNAs (mRNAs), un-spliced pre-mRNAs and mRNA splicing machinery, as well as all the necessary molecular and cellular components to support translation of mRNA into protein, and to degrade existing proteins. Platelet reactivity, hemostatic capacity and thrombotic potential vary widely in humans, and we are investigating how control of protein translation contributes to this variation.
Although mRNA translation in platelets (despite an inability to generate new mRNAs) was recognized many years ago, very little remains known about how platelets translate new protein necessary for their ongoing metabolism and reactivity while in circulation. We are exploring the molecular signaling controlling mRNA translation in circulating platelets, including the roles of platelet miRNAs, and the cellular and physiological outcomes and effects. Based on these mechanistic studies, we are developing translational approaches to control platelet reactivity via miRNA manipulation and other approaches in multiple contexts.
Platelet-derived extracellular vesicles
Beyond direct roles for platelets in hemostasis and thrombosis, these cells release extracellular vesicles (EVs) into the bloodstream which support intercellular communication in many contexts, via surface contact of platelet-derived EVs with distal cells, as well as transfer of platelet-derived material by EV uptake in the target cells. Platelet-derived EVs and their contents are both markers and mediators of physiological response, including immune response. We are investigating the molecular and cellular mechanisms of EV generation by platelets, and their downstream effects in various settings.