The broad long-term goals of this project are to define mechanisms by which interactions between myeloid leukocytes, endothelial cells and platelets activate molecular pathways that regulate cellular function and phenotype, how these functions become dysregulated, and how dysregulated interactions and activities cause inflammatory vascular and tissue injury. Molecular mechanisms and pathways that control these events provide fundamental biologic insights;in addition, they are directly relevant to human disease, since dysregulated inflammatory cell-cell interactions are key features of major human syndromes that span a spectrum from the acute manifestations of sepsis to atherosclerosis and its complications. After initially characterizing key mechanisms of myeloid leukocyte tethering and adhesion, work in this project has focused on how outside-in signals delivered by these adhesion pathways and by inflammatory receptors lead to altered gene expression. In the last funding period we explored post-transcriptional mechanisms of gene regulation, an issue of evolving significance in human biology and disease in the post-genomic era, and have identified pathways for signal-dependent translation of critical messenger RNAs (mRNAs) in myeloid leukocytes, endothelial cells and platelets that were previously unrecognized and have physiologic significance. The current application builds on these discoveries, and will characterize novel signal- dependent translation pathways and genes based on the central hypothesis that translational control and signal-dependent translation mechanisms regulate key innate immune cell phenotypes, functions and responses in acute and chronic inflammation.
The specific aims are: 1) to characterize inflammatory mechanisms that regulate the mTOR translational control pathway in myeloid leukocytes;2) define new inflammatory activities of mTOR in specialized innate immune effector cells;3) characterize novel signal- dependent translation mechanisms in myeloid leukocytes;4) test the hypothesis that translationally- regulated genes in myeloid leukocytes comprise a sub-group of transcripts that code for critical inflammatory proteins and can be identified by their association with polyribosomes. The studies will resolve critical gaps in our knowledge of gene regulation in inflammatory systems, have direct clinical relevance, and are innovative because they explore new concepts and paradigms.
|Hottz, Eugenio D; Medeiros-de-Moraes, Isabel M; Vieira-de-Abreu, Adriana et al. (2014) Platelet activation and apoptosis modulate monocyte inflammatory responses in dengue. J Immunol 193:1864-72|
|Floyd, Robert A; Castro Faria Neto, Hugo C; Zimmerman, Guy A et al. (2013) Nitrone-based therapeutics for neurodegenerative diseases: their use alone or in combination with lanthionines. Free Radic Biol Med 62:145-56|
|Weyrich, Andrew S; Zimmerman, Guy A (2013) Platelets in lung biology. Annu Rev Physiol 75:569-91|
|Gomes, Rachel N; Teixeira-Cunha, Mariana G A; Figueiredo, Rodrigo T et al. (2013) Bacterial clearance in septic mice is modulated by MCP-1/CCL2 and nitric oxide. Shock 39:63-9|
|Schmid, Douglas I; Schwertz, Hansjorg; Jiang, Huimiao et al. (2013) Translational control of JunB, an AP-1 transcription factor, in activated human endothelial cells. J Cell Biochem 114:1519-28|
|Harris, Estelle S; Weyrich, Andrew S; Zimmerman, Guy A (2013) Lessons from rare maladies: leukocyte adhesion deficiency syndromes. Curr Opin Hematol 20:16-25|
|Rondina, Matthew T; Weyrich, Andrew S; Zimmerman, Guy A (2013) Platelets as cellular effectors of inflammation in vascular diseases. Circ Res 112:1506-19|
|Vieira-de-Abreu, Adriana; Campbell, Robert A; Weyrich, Andrew S et al. (2012) Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum. Semin Immunopathol 34:5-30|
|Rondina, Matthew T; Wanner, Nathan; Pendleton, Robert C et al. (2012) A pilot study utilizing whole body 18 F-FDG-PET/CT as a comprehensive screening strategy for occult malignancy in patients with unprovoked venous thromboembolism. Thromb Res 129:22-7|
|Jiang, Huimiao; Schwertz, Hansjorg; Schmid, Douglas I et al. (2012) Different mechanisms preserve translation of programmed cell death 8 and JunB in virus-infected endothelial cells. Arterioscler Thromb Vasc Biol 32:997-1004|
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