Research Interests

The main focus of our research is the identification and characterization of the signaling pathways regulating the activation of NADPH oxidase in endothelial cells. In particular, we are interested in the role that PI3Ks and SHIPs have in the production of phosphatidylinositols (PIPs) by proinflammatory mediators which leads to the activation of NADPH oxidase-induced ROS production. Our recent work led to the discovery that TNF{alpha}can signal through a non G-protein coupled receptor to induce PIP production in the endothelium which leads to an increase in neutrophil-mediated lung injury. The overall hypothesis to be tested is that a balance between a positive PI3K-induced signal and a negative SHIP2-induced signal serves to regulate NADPH oxidase activation in ECs, and therefore this balance is crucial to the mechanism of lung injury.

The other focus of this lab is to understand the neutrophil-endothelial cell “cross-talk” that leads to an increase in ROS production in ECs. Interactions of polymorphonuclear neutrophils with endothelial cells may contribute to the activation of endothelial cell responses involved in innate immunity. PMN NADPH oxidase-derived oxidant signaling is an important determinant of the cross talk between TLR4 and TLR2 and the control of endothelial cell activation.

4020 CoMRB
909 S. Wolcott Ave.
(312) 413-3428
rfrey@uic.edu

• Frey, RS, Gao, X-P, Javaid, K, Siddiqui SS, Rahman A, Malik, AB. Phosphatidylinositol 3-kinase gamma signaling through PKCzeta induces NADPH oxidase-mediated oxidant generation and NF-kappa B activation in endothelial cells, Journal of Biological Chemistry, 281(23)16128-38, 2006.
• Zhao, Y-Y, Gao, X-P, Zhao, Y-D, Mirza, MK, Frey, RS, Kalinichenko, VV, Wang, I-C, Costa, RH, Malik, AB Endothelial cell-restricted disruption of FoxM1 impairs endothelial repair following vascular injury induced by lipopolysaccharide, The Journal of Clinical Investigation, 116(9)2333-2343, 2006.
• Gao, XP, Zhu, X, Fu, J, Liu, Q, Frey, RS, Malik, AB. Blockade of class IA phosphoinositide 3-kinase in neutrophils prevents NADPH oxidase activation- and adhesion-dependent inflammation, Journal of Biological Chemistry, In Press, 2006.
• Wang Y, Keogh RJ, Hunter MG, Mitchell CA, Frey RS, Javaid K, Malik AB, Schurmans S, Tridandapani S, Marsh CB, SHIP2 is recruited to the cell membrane upon macrophage colony-stimulating factor (M-CSF) stimulation and regulates M-CSF-induced signaling, Journal of Immunology, 173(11):6820-30, Dec 2004
• Fan J, Frey RS, Malik AB, TLR4 Signaling Induces TLR2 Expression in Endothelial Cells Via Neutrophil NADPH Oxidase., The Journal of Clinical Investigation, 112(8):1234-43, 2003.
• Fan J, Frey RS, Rahman A, Malik AB, Role of neutrophil NADPH oxidase in the mechanism of tumor necrosis factor-alpha-induced NF-kappa B activation and intercellular adhesion molecule-1 expression in endothelial cells, Journal of Biological Chemistry, 277(5):3404-11, February 2002.