We study the pathways and mechanisms underpinning platelet and megakaryocyte functions in health and disease. We have a particular emphasis on cellular and host responses during infectious, inflammatory, and thrombotic diseases. We couple human studies with in vitro and in vivo model systems for bench-to-bedside translational work. We also apply technologies such as next-generation RNA sequencing and ribosomal footprinting to understand the regulation of global and targeted gene expression in megakaryocytes and platelets. In some studies, we also examine interactions between platelets and other circulating blood cells (e.g. leukocytes, lymphocytes, others). Below are several active areas of investigation in our laboratory.
Inflammatory Stressors and Gene Expression
Our lab is a leader in dissecting how inflammation alters the expression of RNAs, proteins, and regulatory elements in megakaryocytes and platelets. We utilize murine models, in vitro systems, and patient samples to discover how acute and chronic inflammatory stressors modulate gene expression and downstream functional responses. Our active projects include experimental and clinical studies in sepsis, vasculitis, HIV, and other settings where inflammation and thrombosis are common.
Thrombosis, Inflammation, and Aging
Aging is characterized by a markedly increased thrombosis risk, including cardiovascular disease, stroke, and venous thromboembolism. Heightened inflammation during aging is thought to contribute to this risk, but remains incompletely understood. Funded through the NIA/NIAID, we have created a publicly-available dataset identifying differentially expressed mRNAs in aging. We have also identified previously-unknown proteins altered in aging and demonstrated their impact on the synthesis of inflammatory proteins by target leukocytes.
Platelet Immune Activities
Emerging studies highlight that while anucleate, platelets possess a dynamic repertoire of functions that span inflammatory and immune activities. Driven by our interest in understanding non-canonical roles of platelets and megakaryocytes, we have developed toolsets enabling us to interrogate and manipulate innate and adaptive immune functions held by platelets and megakaryocytes.
Translational Control Mechanisms
The mechanisms regulating gene expression in platelets and megakaryocytes remains only partially understood. Our active projects span the breadth of transcriptional control to post-translational modification of de novo proteins. Our discoveries indicate that traditionally nuclear elements, including retinoic acid receptors and LINE-1 encoded reverse transcriptase, are present and functional in platelets. We are also dissecting previously-unknown translational control pathways in platelets and megakaryocytes, including DNA-RNA hybrid formation and MAPK-kinase interacting kinase (Mnk1/2).