Department of Cellular and Molecular Medicine
Paul E. DiCorleto, Ph.D.
Lerner Research Institute
9500 Euclid Avenue
Cleveland, Ohio 44195
Phone: (216) 444-5849
Fax: (216) 444-3279
The central objective of our research is to understand the role of endothelial cell (EC) gene expression in the maintenance of healthy blood vessels and in the genesis of vascular diseases. We are pursing the thrombin- and cytokine-activated intracellular signaling pathways and transcription factors responsible for induction of pro-inflammatory events, including leukocyte adhesion to EC, in vivo and in vitro. We are currently focused on the relative importance of the two tumor necrosis factor (TNF)-alpha receptors in EC activation and in such diseases as atherosclerosis and psoriasis. We are elucidating the specific signaling pathways triggered by each receptor that must combine to generate the inflammatory response. We are also studying the role of the homeobox transcription factor HOXA9 and its binding partner protein arginine methyl transferase 5 (PRMT5) in the induction of proinflammatory genes in EC. Finally, we are characterizing regulatory pathways involved in the expression of inflammatory genes and induction of angiogenesis by EC in response to the protease thrombin and the angiogenic factor VEGF and defining the induction and functions of the dual-specificity nuclear phosphatase MKP-1 (MAP kinase phosphatase-1). An overriding goal of the research program is to identify novel targets for anti-inflammation therapy.
Kinney, C.M., Chandrasekharan, U.M., Yang, L., Shen, J., Kinter, M., McDermott, M.S. and DiCorleto, P.E. (2009) Histone H3 as a novel substrate for MAP Kinase Phosphatase 1. Am. J. Physiol. Cell Physiol. 296: C242-249.
Shen, J., Chandrasekharan, U.M., Ashraf, M.Z., Long, E., Morton, R.E., Liu, Y., Smith, J.D. and DiCorleto, P.E. (2010) Lack of MKP-1 protects ApoE-null mice against atherosclerosis. Circ Res. 106(5):902-910.
Chandrasekharan, U.M., Waitkus, M., Kinney, C.M., Walters-Stewart, A., and DiCorleto, P.E. (2010). Synergistic induction of MKP-1 by thrombin and epidermal growth factor requires vascular endothelial growth factor receptor-2. Arterioscler Thromb Vasc Biol. 30:1983-1989.
Bandyopadhyay, S., Harris, D.P., Adams, G.N., Lause, G.E., McHugh, A., Tillmaand, E.G., Money, A., Willard, B., Fox, P.L., and DiCorleto, P.E. (2012) HOXA9 methylation by PRMT5 is essential for endothelial cell expression of leukocyte adhesion molecules. Mol Cell Biol. 32:1202-13.