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.
|Schwertz, Hansjörg; Rowley, Jesse W; Schumann, Gerald G et al. (2018) Endogenous LINE-1 (Long Interspersed Nuclear Element-1) Reverse Transcriptase Activity in Platelets Controls Translational Events Through RNA-DNA Hybrids. Arterioscler Thromb Vasc Biol 38:801-815|
|Middleton, Elizabeth A; Rondina, Matthew T; Schwertz, Hansjorg et al. (2018) Amicus or Adversary Revisited: Platelets in Acute Lung Injury and Acute Respiratory Distress Syndrome. Am J Respir Cell Mol Biol 59:18-35|
|Nascimento, Danielle de Oliveira; Vieira-de-Abreu, Adriana; Arcanjo, Angélica F et al. (2018) Integrin ?D?2 (CD11d/CD18) Modulates Leukocyte Accumulation, Pathogen Clearance, and Pyroptosis in Experimental Salmonella Typhimurium Infection. Front Immunol 9:1128|
|Campbell, Robert A; Vieira-de-Abreu, Adriana; Rowley, Jesse W et al. (2017) Clots Are Potent Triggers of Inflammatory Cell Gene Expression: Indications for Timely Fibrinolysis. Arterioscler Thromb Vasc Biol 37:1819-1827|
|Rodrigues, Rosana S; Bozza, Fernando A; Hanrahan, Christopher J et al. (2017) 18 F-fluoro-2-deoxyglucose PET informs neutrophil accumulation and activation in lipopolysaccharide-induced acute lung injury. Nucl Med Biol 48:52-62|
|de Azevedo-Quintanilha, Isaclaudia G; Vieira-de-Abreu, Adriana; Ferreira, André Costa et al. (2016) Integrin ?D?2 (CD11d/CD18) mediates experimental malaria-associated acute respiratory distress syndrome (MA-ARDS). Malar J 15:393|
|Middleton, Elizabeth A; Weyrich, Andrew S; Zimmerman, Guy A (2016) Platelets in Pulmonary Immune Responses and Inflammatory Lung Diseases. Physiol Rev 96:1211-59|
|Rondina, M T; Freitag, M; Pluthero, F G et al. (2016) Non-genomic activities of retinoic acid receptor alpha control actin cytoskeletal events in human platelets. J Thromb Haemost 14:1082-94|
|Yost, Christian C; Schwertz, Hansjörg; Cody, Mark J et al. (2016) Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation. J Clin Invest 126:3783-3798|
|Araújo, Cláudia V; Campbell, Clarissa; Gonçalves-de-Albuquerque, Cassiano F et al. (2016) A PPAR? AGONIST ENHANCES BACTERIAL CLEARANCE THROUGH NEUTROPHIL EXTRACELLULAR TRAP FORMATION AND IMPROVES SURVIVAL IN SEPSIS. Shock 45:393-403|
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