Person: Carman, Christopher
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Carman
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Christopher
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Carman, Christopher
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Publication Actin foci facilitate activation of the phospholipase C-γ in primary T lymphocytes via the WASP pathway(eLife Sciences Publications, Ltd, 2015) Kumari, Sudha; Depoil, David; Martinelli, Roberta; Judokusumo, Edward; Carmona, Guillaume; Gertler, Frank B; Kam, Lance C; Carman, Christopher; Burkhardt, Janis K; Irvine, Darrell J; Dustin, Michael LWiscott Aldrich Syndrome protein (WASP) deficiency results in defects in calcium ion signaling, cytoskeletal regulation, gene transcription and overall T cell activation. The activation of WASP constitutes a key pathway for actin filament nucleation. Yet, when WASP function is eliminated there is negligible effect on actin polymerization at the immunological synapse, leading to gaps in our understanding of the events connecting WASP and calcium ion signaling. Here, we identify a fraction of total synaptic F-actin selectively generated by WASP in the form of distinct F-actin ‘foci’. These foci are polymerized de novo as a result of the T cell receptor (TCR) proximal tyrosine kinase cascade, and facilitate distal signaling events including PLCγ1 activation and subsequent cytoplasmic calcium ion elevation. We conclude that WASP generates a dynamic F-actin architecture in the context of the immunological synapse, which then amplifies the downstream signals required for an optimal immune response. DOI: http://dx.doi.org/10.7554/eLife.04953.001Publication Soluble adhesion molecules as markers for sepsis and the potential pathophysiological discrepancy in neonates, children and adults(BioMed Central, 2014) Zonneveld, Rens; Martinelli, Roberta; Shapiro, Nathan; Kuijpers, Taco W; Plötz, Frans B; Carman, ChristopherSepsis is a severe and life-threatening systemic inflammatory response to infection that affects all populations and age groups. The pathophysiology of sepsis is associated with aberrant interaction between leukocytes and the vascular endothelium. As inflammation progresses, the adhesion molecules that mediate these interactions become shed from cell surfaces and accumulate in the blood as soluble isoforms that are being explored as potential prognostic disease biomarkers. We critically review the studies that have tested the predictive value of soluble adhesion molecules in sepsis pathophysiology with emphasis on age, as well as the underlying mechanisms and potential roles for inflammatory shedding. Five soluble adhesion molecules are associated with sepsis, specifically, E-selectin, L-selectin and P-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. While increased levels of these soluble adhesion molecules generally correlate well with the presence of sepsis, their degree of elevation is still poorly predictive of sepsis severity scores, outcome and mortality. Separate analyses of neonates, children and adults demonstrate significant age-dependent discrepancies in both basal and septic levels of circulating soluble adhesion molecules. Additionally, a range of both clinical and experimental studies suggests protective roles for adhesion molecule shedding that raise important questions about whether these should positively or negatively correlate with mortality. In conclusion, while predictive properties of soluble adhesion molecules have been researched intensively, their levels are still poorly predictive of sepsis outcome and mortality. We propose two novel directions for improving clinical utility of soluble adhesion molecules: the combined simultaneous analysis of levels of adhesion molecules and their sheddases; and taking age-related discrepancies into account. Further attention to these issues may provide better understanding of sepsis pathophysiology and increase the usefulness of soluble adhesion molecules as diagnostic and predictive biomarkers.Publication Release of cellular tension signals self-restorative ventral lamellipodia to heal barrier micro-wounds(The Rockefeller University Press, 2013) Martinelli, Roberta; Kamei, Masataka; Sage, Peter; Massol, Ramiro; Varghese, Laya; Sciuto, Tracey; Toporsian, Mourad; Dvorak, Ann; Kirchhausen, Tomas; Springer, Timothy; Carman, ChristopherBasic mechanisms by which cellular barriers sense and respond to integrity disruptions remain poorly understood. Despite its tenuous structure and constitutive exposure to disruptive strains, the vascular endothelium exhibits robust barrier function. We show that in response to micrometer-scale disruptions induced by transmigrating leukocytes, endothelial cells generate unique ventral lamellipodia that propagate via integrins toward and across these “micro-wounds” to close them. This novel actin remodeling activity progressively healed multiple micro-wounds in succession and changed direction during this process. Mechanical probe-induced micro-wounding of both endothelia and epithelia suggests that ventral lamellipodia formed as a response to force imbalance and specifically loss of isometric tension. Ventral lamellipodia were enriched in the Rac1 effectors cortactin, IQGAP, and p47Phox and exhibited localized production of hydrogen peroxide. Together with Apr2/3, these were functionally required for effective micro-wound healing. We propose that barrier disruptions are detected as local release of isometric tension/force unloading, which is directly coupled to reactive oxygen species–dependent self-restorative actin remodeling dynamics.Publication T Lymphocyte–Endothelial Interactions: Emerging Understanding of Trafficking and Antigen-Specific Immunity(Frontiers Media S.A., 2015) Carman, Christopher; Martinelli, RobertaAntigen-specific immunity requires regulated trafficking of T cells in and out of diverse tissues in order to orchestrate lymphocyte development, immune surveillance, responses, and memory. The endothelium serves as a unique barrier, as well as a sentinel, between the blood and the tissues, and as such it plays an essential locally tuned role in regulating T cell migration and information exchange. While it is well established that chemoattractants and adhesion molecules are major determinants of T cell trafficking, emerging studies have now enumerated a large number of molecular players as well as a range of discrete cellular remodeling activities (e.g., transmigratory cups and invadosome-like protrusions) that participate in directed migration and pathfinding by T cells. In addition to providing trafficking cues, intimate cell–cell interaction between lymphocytes and endothelial cells provide instruction to T cells that influence their activation and differentiation states. Perhaps the most intriguing and underappreciated of these “sentinel” roles is the ability of the endothelium to act as a non-hematopoietic “semiprofessional” antigen-presenting cell. Close contacts between circulating T cells and antigen-presenting endothelium may play unique non-redundant roles in shaping adaptive immune responses within the periphery. A better understanding of the mechanisms directing T cell trafficking and the antigen-presenting role of the endothelium may not only increase our knowledge of the adaptive immune response but also empower the utility of emerging immunomodulatory therapeutics.Publication ERG is Required for the Differentiation of Embryonic Stem Cells along the Endothelial Lineage(BioMed Central, 2009) Nikolova-Krstevski, Vesna; Yuan, Lei; Le Bras, Alexandra; Vijayaraj, Preethi; Kondo, Maiko; Gebauer, Marie-Isabel; Bhasin, Manoj; Carman, Christopher; Oettgen, PeterBackground: The molecular mechanisms that govern stem cell differentiation along the endothelial lineage remain largely unknown. Ets related gene (ERG) has recently been shown to participate in the transcriptional regulation of a number of endothelial specific genes including VE-cadherin (CD144), endoglin, and von Willebrand's Factor (vWF). The specific role of the ETS factor ERG during endothelial differentiation has not been evaluated. Results: ERG expression and function were evaluated during the differentiation of embryonic stem cells into embryoid bodies (EB). The results of our study demonstrate that ERG is first expressed in a subpopulation of vascular endothelial growth factor receptor 2 (VEGF-R2) expressing cells that also express VE-cadherin. During ES cell differentiation, ERG expression remains restricted to cells of the endothelial lineage that eventually coalesce into primitive vascular structures within embryoid bodies. ERG also exhibits an endothelial cell (EC)-restricted pattern during embryogenesis. To further define the role of ERG during ES cell differentiation, we used a knockdown strategy to inhibit ERG expression. Delivery of three independent shRNA led to 70-85% reductions in ERG expression during ES cell differentiation compared to no change with control shRNA. ERG knockdown was associated with a marked reduction in the number of ECs, the expression of EC-restricted genes, and the formation of vascular structures. Conclusion: The ETS factor ERG appears to be a critical regulator of EC differentiation.