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 publications, contact information Research Interests My laboratory is interested in different aspects of innate immunity, in the context of inflammation, infectious disease, and cancer. The following projects are currently ongoing: 1. Contribution of cyclophilins to inflammatory diseases: Extracellular cyclophilins are present at very elevated levels in many inflammatory diseases and have recently been shown to have potent chemotactic properties. We are investigating whether these cyclophilins might contribute to inflammatory processes by promoting leukocyte recruitment into inflamed tissues. Animal models of acute lung injury, acute and chronic allergic asthma, and rheumatoid arthritis are being used to assess the impact of inhibiting the function of extracellular cyclophilins on tissue inflammation and pathology. In addition, we are investigating the interaction between extracellular cyclophilins and other chemokines known to be present during inflammatory responses. This project is being conducted in collaboration with Dr. Michael Bukrinsky (MITM). 2. Contribution of inflammation to lung cancer development: Compounds containing hexavalent chromium metals, Cr(VI), have been designated as environmental and occupational carcinogens by the EPA and OSHA. Studies have shown that long-term inhalational exposure to Cr(VI) can lead to the development of lung cancer as well as other lung diseases, including allergic asthma. My laboratory recently established a new mouse model of chronic pulmonary exposure to Cr(VI) that will enable us to investigate the factors that regulate the development of lung cancer to Cr(VI)-containing compounds and whether asthma mediated lung inflammation is a contributing factor. These studies are being conducted in collaboration with Drs. Susan Ceryak and Steven Patierno (PHARM and GW Cancer Institute). 3. Hookworm secretions and host immunomodulation: We have recently identified a protein(s) secreted by Necator americanus hookworm parasites that binds selectively to human natural killer (NK) cells and induces them to secrete high levels of IFNg. Studies are currently underway to characterize this NK cell binding protein (NKBP) and identify its receptor on NK cells. In addition, we are investigating the binding and effect of NKBP on leukocytes from patients with active hookworm infections in Brazil to establish the physiologic contribution of this protein(s) to the maintenance of chronic hookworm infection. This project is being conducted in collaboration with Drs. Jeff Bethony (MITM) and Alex Loukas (QIMR, Australia). Selected Publications Top Beaver, L., E. Stemmy, S. Constant, A. Schwartz, L. Little, K. Sugden, S. Ceryak and S. Patierno. 2009. Lung injury, inflammation and AKT signaling following inhalation of particulate hexavalent chromium. Tox. App. Pharm. 235:47-56. Damsker, J., I. Okwumabua, T. Pushkarsky, K. Arora, M. Bukrinsky and S. Constant. 2008. Targeting the chemotactic function of CD147 reduces collagen-induced arthritis. Immunology 126:55-62. Teixeira-Carvalho, A., R. Fujiwara, E. Stemmy, D. Olive, J. Damsker, A. Loukas, R. Correa-Oliveira, S. Constant* and J. Bethony*. 2008. Binding of excreted/secreted products of adult Necator americanus to human NK cells in hookworm infected individuals from Brazil. Inf. Immun. 76:5810-5816. (*Joint senior authors) Choi, E., E. Chavakis, M. Czabanka, H. Langer, M. Economopoulou, L. Fraemohs, A. Orlandi, R. Kundu, Y. Zheng, C. Ballantyne, S. Constant, W. Aird, C. Gahmberg, M. Udey, C. Weber, P. Vajkoczy, T. Quertemous, S. Dimmeler and T. Chavakis. 2008. Del-1 is an endogenous inhibitor of leukocyte-endothelial adhesion preventing inflammatory cell recruitment. Science 322:1101-1104. Bower, M., S. Constant and S. Mendez. 2008. Necator americanus: The Na-ASP2 protein secreted by the infective larvae induces neutrophil recruitment in vivo and in vitro in a murine model of air pouch inflammation. Exp. Parasitol. 118:569-575. Damsker, J., M. Bukrinsky and S. Constant. 2007. Extracellular cyclophilin A induces CD147-dependent migration of human CD4 + T lymphocytes. J. Leuk. Biol. 82:613-618. Yamashita, Y., N. Charles, Y. Furumoto, S. Odom, T. Yamashita, A. Gilfillan, S. Constant, M. Bower, J. Ryan and J. Rivera. 2007. Cutting Edge: Genetic variation influences Fc e RI-induced mast cell activation and allergic responses. J. Immunol. 179:740-743. Wolnicka-Glubisz, A., J. Damsker, S. Constant, S. Corn, E. De Fabo and F. Noonan. 2007. Deficient inflammatory response to UVB in neonatal mice. J. Leuk. Biol. 81:1352-1361. Gwinn, W., J. Damsker, R. Falahati, I. Okwumabua, A. Kelly-Welsh, A. Keegan, C. Vanpouille, J. Lee, L. Dent, D. Leitenberg, M. Bukrinsky and S. Constant. 2006. Novel approach to inhibit asthma-mediated lung inflammation using anti-CD147 intervention. J. Immunol. 177:4870-4879. Cormier, S., A. Taranova, C. Bedient, T. Nguyen, C. Protheroe, R. Pero, D. Dimina, S. Ochkur, K. O’Neill, D. Colbert, T. Lombari, S. Constant, M. McGarry, J. Lee and N. Lee. 2006. Eosinophil infiltration of solid tumors is an early and persistent inflammatory host response. J. Leuk. Biol. 79: 1131-1139. Yurchenko, V., S. Constant and M. Bukrinsky. 2006. Dealing with the Family: CD147 interactions with cyclophilins. Immunology 117:301-309. Contact Information Top The George Washington University Medical Center
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