The broad, long-term goal of our group is to characterize prolonged responses of platelets that contribute to hemostasis and inflammation. One function that occurs for hours is translation of mRNA into protein, a process that is under discrete regulatory control. During the last funding period we demonstrated that platelets possess a functional spliceosome, an observation that established several new paradigms. First, it demonstrated that pre-mRNA splicing is not exclusively a nuclear process. Second, it introduced cytoplasmic pre-mRNA splicing as a new checkpoint of post-transcriptional gene expression. Lastly, it identified a new function of platelets that contributes to thrombosis and inflammation. The presence of an active mRNA editing complex in platelets demonstrates that this anucleate cytoplast uses complex systems to accumulate protein. It also suggests that platelets use their protein synthetic machinery for phenotypic alterations that are yet to be discovered. Here, we put forth the hypothesis that protein synthesis plays an important role in the generation of progeny, a previously-unrecognized function of anucleate platelets. We propose two specific aims to test our central hypothesis.
In aim 1 we will characterize progeny formation by freshly-isolated and ex vivo aged platelets and will determine if platelets use their protein synthetic machinery to generate daughter cells.
In aim 2 we will determine if this process is regulated by endogenous reverse transcriptase (RT), a key regulator of cellular differentiation. We will determine the source of RT activity in platelets and whether endogenous RT regulates protein synthesis and progeny formation in human platelets. Our two aims fundamentally challenge the dogma that platelets are fully differentiated cells that are incapable of generating progeny. Our proposed studies also focus on a previously-unrecognized function of platelets that likely has physiologic and/or pathologic consequences.
Platelets are one of the most abundant cells in the circulation whose primary function is to halt blood flow at sites of injury. Platelet counts vary among human subjects and when they get too low, patients tend to bleed and suffer complications that are life threatening. In this proposal, we explore a brand new function of platelets that allows them to regenerate in the circulation. The results of our studies will have immediate clinical impact in regards to how platelet counts are controlled in human subjects. Our findings are also likely to identify new targets for the treatment of thrombocytopenia and the expansion of platelets used for transfusion medicine.
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|Harris, Estelle S; Weyrich, Andrew S; Zimmerman, Guy A (2013) Lessons from rare maladies: leukocyte adhesion deficiency syndromes. Curr Opin Hematol 20:16-25|
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