The Molecular Regulation of Platelet Reprogramming by the Metabolic Milieu

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PROJECT SUMMARY (See instructions): The central hypothesis of the University of Utah Molecular Medicine Translation Research Center in Thrombosis (U2M2-TRCT) is that the systemic metabolic milieu reprograms platelets into cells that display a prothrombotic phenotype. As part of this programmatic theme, project 1 will begin defining the molecular mechanisms that control reprogramming events in megakaryocytes and platelets. Project 1 is supported by next-generation RNA-sequencing and functional data in platelets isolated from obese and diabetic humans and mice. Specifically, we show that the metabolic milieu induces profound changes in the molecular signature and function of platelets. It is our contention that these changes are not random: instead, we believe that distinct molecular mechanisms reprogram gene expression in megakaryocytes and platelets. One control checkpoint, which we will test in project 1, involves regulation by microRNAs (miRNAs). ' Three specific aims will be used to examine how obesity and diabetes reprograms the molecular signature and function of platelets. In the first aim and in coordination with project 2, we will determine if diet-induced obesity, obesity followed by weight loss, and therapeutic correction of systemic metabolic imbalances alters reprogramming events in mouse platelets. The first aim will also incorporate corollary studies in human patients with metabolic syndrome. In aim 2, we will determine the role of precursor miRNA processing in regulating platelet reprogramming and function using mice whose platelets lack Dicer, an RNase III enzyme that is central to the production of mature miRNAs. In the final aim, we will determine how miRNAs regulate the expression of mitochondrial transcripts/proteins (uncoupling protein 2 and mitofusin 2) that are upregulated in platelets isolated from obese mice and humans. Data generated from Aim 3 will directly compliment project 2, which tests the functionality of these mitochondrial targets, and projects 3 and 4 that characterize their expression patterns in platelets isolated from humans with metabolic syndrome. Thus, project 1 will contribute to all facets of the U2M2-TRCT program as it reveals new insights into how the metabolic milieu influences the molecular signature and function of platelets.