Bsc (Hons): Physiology and Biochemistry University of Reading, U.K. (1990)
Ph.D. Vascular Biology. King's College London, UK (1994).

Vascular endothelial cells (EC) form the innermost lining of the blood vessel wall where, virtue of their location, EC play an important function in permeability of macromolecules, vasoregulation and prevention of coagulation. EC are also positioned to respond to a wide variety of stimuli such as hormones, peptides and pro-inflammatory cytokines and play a major role in initiation of hemostasis and inflammation. My research has largely focused on the effects of cytokines of the TNF superfamily such as TNF, LIGHT and lymphotoxin as well as IL-1 on EC function. The effects of these cytokines are directly involved in the pathogenesis of sepsis, vascular leak, atherosclerosis and transplant rejection. While the initial effects of these cytokines on EC is to induce new gene expression, a common feature in the progression of all such pathological processes is endothelial injury. My research has therefore focused in two areas:

1. Understanding the signaling pathways that regulate cytokine-induced gene activation. In collaboration with Dr. Michael May, we are investigating the regulation and function of the NFkappaB transcription factor in EC.

2. Understanding the signaling pathways that regulate cytokine-dependent cell death in EC. I am investigating the regulation of programmed cell death (apoptosis) in EC. These studies are focused on determining the mechanisms through which cytokine receptor ligation may initiate cell death (e.g. through the activation of caspases and cathepsins) or inhibit the process (e.g. though the induction or modification of anti-apoptotic proteins).

Madge, L.A . and May, M.J. LIGHT and lymphtoxina1b2 activate classical and non-canonical NFkappaB and induce pro-inflammatory and lymphoid-specific gene expression in human umbilical vein endothelial cells. (submitted).

May M.J., Larsen S.E., Shim J.H., Madge L.A., Ghosh S . A novel ubiquitin-like domain in IkappaB kinase beta is required for functional activity of the kinase. J Biol Chem. 279(44):45528-39 (2004).

Siwkowski A.M., Madge L.A., Koo S, McMillan E.L., Monia B.P., Pober J.S., Baker B.F. Effects of antisense oligonucleotide-mediated depletion of tumor necrosis factor (TNF) receptor 1-associated death domain protein on TNF-induced gene expression. Mol Pharmacol. 66(3):572-9 (2004).

Madge, L.A . , Li, J-H., Choi, J and Pober, J.S. Inhibition of PI-3 kinase sensitizes vascular endothelial cells to cytokine-initiated cathepsin-dependent apoptosis. J. Biol. Chem 278 21295-21306 (2003).

Li, J-H, Kluger M.S., Madge, L.A . , Zheng, L., Bothwell, A.L.M. and Pober, J.S. IFN- g augments CD95(APO-1/Fas) and pro-caspase-8 expression and sensitizes human vascular endothelial cells to CD-95-mediated apoptosis. Am. J. Pathol 161 (4) 1485-1495 (2002).

Feng, X., Gaeta , M-L., Madge, L.A. , Yang, J-H., Bradley, J.R., and Pober, J.S. Caveolin-1 associates with TRAF2 to form a complex that is recruited to TNF receptors. J. Biol. Chem. 276(11): 8341-8349 (2001).

May, M.J., D’Acquisto, F., Madge, L.A . , Gloekner, J., Pober, J.S. and Ghosh, S. Selective inhibition of cytokine-mediated NF- k B activation by a peptide that blocks the interaction of NEMO with the I k B kinase complex. Science289(5484): 1550-1554 (2000).

Madge L.A . and Pober J.S. A PI-3 Kinase/Akt Pathway, Activated By TNF or IL-1 Inhibits Apoptosis But Does Not Activate NF k B in Human Endothelial Cells. J. Biol. Chem. 275: 15458-15465 (2000).

Zheng, L., Dengler T.J., Kluger M.S., Madge L.A., Schechner J.S., Maher S.E., Pober J.S. and Bothwell A.L.M. Cytoprotection of HUVEC against CTL-mediated lysis and apoptosis provided by caspase resistant Bcl-2 without alterations in growth activation or responses. J Immunol. 164(9):4665-71 (2000).

Madge L.A., Sierra-Honigmann M.R. and Pober J.S. Structurally diverse apoptosis-inducing agents cause a rapid loss of TNFR1 expression: A non-pharmacological explanation for inhibition of TNF-mediated endothelial activation. J. Biol. Chem. 274 (19):13643-9, (1999).

Sierra-Honigmann M.R., Nath A.K., Murakami C., Garcia-Cardena G., Papapetropoulos A., Sessa W.C., Madge L.A., Schechner J.S., Schwabb M.B., Polverini P.J. and Flores-Riveros J.R. Biological action of leptin as an angiogenic factor. Science 281(5383):1683-6 (1998).

Madge L.A., Marshall I.C.B. and Taylor C.W. Delayed autoregulation of Ca 2+ signals resulting from capacitative Ca 2+ entry in bovine pulmonary artery endothelial cells. Journal of Physiology498 (2) p351-369 (1997).