Browsing by Author "Mitrophanov, Alexander Y"
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- ItemComputational approach to characterize causative factors and molecular indicators of chronic wound inflammation.(2014-02-10) Nagaraja, Sridevi; Wallqvist, Anders; Reifman, Jaques; Mitrophanov, Alexander YChronic inflammation is rapidly becoming recognized as a key contributor to numerous pathologies Despite detailed investigations understanding of the molecular mechanisms regulating inflammation is incomplete Knowledge of such critical regulatory processes and informative indicators of chronic inflammation is necessary for efficacious therapeutic interventions and diagnostic support to clinicians We used a computational modeling approach to elucidate the critical factors responsible for chronic inflammation and to identify robust molecular indicators of chronic inflammatory conditions Our kinetic model successfully captured experimentally observed cell and cytokine dynamics for both acute and chronic inflammatory responses Using sensitivity analysis we identified macrophage influx and efflux rate modulation as the strongest inducing factor of chronic inflammation for a wide range of scenarios Moreover our model predicted that among all major inflammatory mediators IL 6 TGF and PDGF may generally be considered the most sensitive and robust indicators of chronic inflammation which is supported by existing but limited experimental evidence
- ItemKinetic model facilitates analysis of fibrin generation and its modulation by clotting factors: implications for hemostasis-enhancing therapies.(2014-07-30) Mitrophanov, Alexander Y; Wolberg, Alisa S; Reifman, JaquesCurrent mechanistic knowledge of protein interactions driving blood coagulation has come largely from experiments with simple synthetic systems which only partially represent the molecular composition of human blood plasma Here we investigate the ability of the suggested molecular mechanisms to account for fibrin generation and degradation kinetics in diverse physiologically relevant in vitro systems We represented the protein interaction network responsible for thrombin generation fibrin formation and fibrinolysis as a computational kinetic model and benchmarked it against published and newly generated data reflecting diverse experimental conditions We then applied the model to investigate the ability of fibrinogen and a recently proposed prothrombin complex concentrate composition PCC AT a combination of the clotting factors II IX X and antithrombin to restore normal thrombin and fibrin generation in diluted plasma The kinetic model captured essential features of empirically detected effects of prothrombin fibrinogen and thrombin activatable fibrinolysis inhibitor titrations on fibrin formation and degradation kinetics Moreover the model qualitatively predicted the impact of tissue factor and tPA tenecteplase level variations on the fibrin output In the majority of considered cases PCC AT combined with fibrinogen accurately approximated both normal thrombin and fibrin generation in diluted plasma which could not be accomplished by fibrinogen or PCC AT acting alone We conclude that a common network of protein interactions can account for key kinetic features characterizing fibrin accumulation and degradation in human blood plasma under diverse experimental conditions Combined PCC AT fibrinogen supplementation is a promising strategy to reverse the deleterious effects of dilution induced coagulopathy associated with traumatic bleeding
- ItemLPS-stimulated NF-κB p65 dynamic response marks the initiation of TNF expression and transition to IL-10 expression in RAW 264.7 macrophages.(0000-00-00) Hobbs, Stuart; Reynoso, Marinaliz; Geddis, Alyssa V; Mitrophanov, Alexander Y; Matheny, Ronald WDuring injury and infection inflammation is a response by macrophages to effect healing and repair The kinetics of the responses of proinflammatory TNF anti inflammatory IL 10 and inflammatory master regulator NF B elicited by lipopolysaccharide LPS may be critical determinants of the inflammatory response by macrophages however there is a lack of homogeneous kinetic data in this pathway To address this gap we used the RAW 264 7 macrophage cell line to define intracellular signaling kinetics and cytokine expression in cells treated with LPS for 15 min to 72 h The abundance of I B was maximally reduced 45 min following LPS treatment but expression increased at 10 h reaching a maximum at 16 h NF B phosphorylation was significantly increased 45 min following LPS treatment maximal at 2 h and decreased to basal levels by 6 h Nuclear NF B expression was elevated 30 min following LPS treatment maximal by 45 min and returned to basal levels by 24 h Binding of nuclear NF B to consensus oligonucleotide sequences followed a similar pattern to that observed for p NF B but lasted slightly longer Following LPS treatment TNF mRNA expression began at 1 h was maximal at 6 h and decreased starting at 10 h TNF protein secretion in conditioned growth medium began at 4 h and was maximal by 16 h IL 10 mRNA expression was induced by LPS at 10 h and was maximal at 16 h IL 10 protein secretion was induced at 16 h and was maximal at 24 h Our data reveal the temporal kinetics of pro and anti inflammatory signaling events that may be important therapeutic targets for inflammatory diseases