Cells of the human body utilize feedback control mechanisms which are known to act on the level of DNA, RNA and protein, in order to maintain and optimize cell metabolism and function. These control mechanisms are commonly referred to as signaling pathways. When cellular homeostasis is disrupted, various signaling pathways are activated by distinct or common stimuli in an attempt to return cellular conditions to a basal state. Disease states typically arise when signaling pathways malfunction, and therefore provide excellent targets for therapeutics. However, due to the non-linear nature of signaling pathways coupled with the limits of current discovery techniques, a majority of active signaling pathways remain unknown. In addition, those pathways that have been investigated remain only partially elucidated, thus making therapeutic discovery very challenging. The process of drug discovery and design may be significantly simplified if potentially therapeutic signaling pathways are identified and manipulated using artificial or natural inducers or inhibitors. To this end, our overall goal is to delineate dominant signal transduction pathways directly involved in the onset of a diseased cellular state. In particular, we aim to identify regulatory molecules (proteins, RNA, chemical entities) that may serve as potential therapeutic targets using computational functional genomics coupled with molecular biology techniques and signal interference technology.
Selected Publications:
Z.R. Healy, F. Zhu, J.D. Stull, and K. Konstantopoulos, "Elucidation of the Signaling Network of Cyclooxygenase-2 (COX-2) Induction in Sheared Chondrocytes: COX-2 Is Induced Via a Rac/MEKK1/MKK7/JNK2/C-Jun-C/EBPß-Dependent Pathway", accepted for publication in The American Journal of Physiology Cell Physiology (March 10, 2008).
P. Jaluria, M.J. Betenbaugh, K. Konstantopoulos, B. Frank, J. Shiloach, "The Use of Microarrays to Identify Genes Involved in Adhesion in HeLa cells and Subsequent Characterization", Metabolic Engineering 9(3); 241-251, 2007. html
P. Jaluria, K. Konstantopoulos, M. Betenbaugh, J. Shiloach, "A Perspective on Microarrays: Current Applications, Pitfalls and Potential Uses", Microbial Cell Factories 6:4, 2007. html
P. Jaluria, M.J. Betenbaugh, K. Konstantopoulos, J. Shiloach, "Enhancement of Cell Proliferation and Protein Production in Various Mammalian Cell Lines by Gene Insertion of a Cyclin-dependent Kinase Homolog, cdkl3", BMC Biotechnology 7:71, 2007. html
P. Jaluria, K. Konstantopoulos, M.J. Betenbaugh, J. Shiloach, "Egr1 and Gas6 Facilitate the Adaptation of HEK-293 Cells to Serum-Free Media by Conferring Enhanced Viability and Higher Growth Rates", accepted for publication to Biotechnology & Bioengineering. 2007. html
Z.R. Healy, N.H. Lee, X. Gao, M.B. Goldring, P. Talalay, T.W. Kensler, K. Konstantopoulos, "Divergent responses of chondrocytes and endothelial cells to shear stress: Cross-talk among COX-2, the phase 2 response, and apoptosis." Proc Natl Acad Sci USA. 102(39); 14010-14015 2005 Sep 27. html
J.P. Abulencia, R. Gaspard, Z.R. Healy, W.A.
Gaarde, J. Quackenbush, K. Konstantopoulos, “Shear-Induced Cyclooxygenase-2
via a JNK2/c-jun-dependent Pathway Regulates Prostaglandin Receptor Expression
in Chondrocytic Cells”, Journal of
Biological Chemistry 278(31); 28388-28394, 2003. html
