Uniformed Services University of the Health Sciences
Department of Pharmacology
4301 Jones Bridge Road
Bethesda, Maryland 20814-4799
Phone: (301) 295-3236
FAX: (301) 295-3220
Cell biology and signal transduction of normal tissue repair and fibrotic remodeling in the lung; adult stem cells that participate in lung repair; anoikis; apoptosis; cytoskeletal rearrangement; cell proliferation; focal adhesion and src kinases; rhoA and Rac1; reactive oxygen species in signal transduction and antioxidant cellular defenses.
Recent findings in fibrotic remodeling diseases of a number of organs including lung, heart, kidney and liver have shown that hepatocyte growth factor (HGF) can mitgate the development of fibrosis, and stimulate normal tissue repair. Our laboratory is interested in identifying HGF signal transduction pathways which lead to normal repair, thus inhibiting fibrotic remodeling by transforming growth factor- beta1 (TGF b1) and angiotensin II (Ang II). Using two animal models for lung fibrosis, the bleomycin model and the thoracic irradiation model, we are exploring changes in protein expression, signal transduction as well as cellular composition of the lung. Our laboratory makes extensive use of primary lung cell culture to study signal transduction by HGF, and mechanisms by which TGF 1 and Ang II signaling for anoikis and apoptosis can be inhibited.
Protection from Acute and Delayed Radiation Toxicity:
Gamma radiation exposure in humans is highly toxic. The injuries induced by radiation have been divided into two categories: acute effects, which often result in lethality within ~30 days, (including the hematopoietic syndrome and the gastrointestinal syndrome); and delayed effects, which may require months to develop (including lung injuries, pneumonitis and pulmonary fibrosis). Our laboratory in collaboration with Dr. Michael R. Landauer at the Armed Forces Radiobiology Research Institute, is investigating the activity and mechanisms of agents to prevent both types of injuries.
Cellular and Molecular Biology
Stacey, D.W., Roudebush, M., Day, R., Mosse, S.C., Gibbs, J.B., Feig, L.A. (1991) Dominant inhibitory Ras mutants demonstrate the requirement for Ras activity in the action of tyrosine kinase oncogenes. Oncogene 6: 2297-2304.
Day, R.M., Cioce, V., Breckenridge, D., Castagnino, P. Bottaro, D.P. (1999) MAP kinase and PI 3-kinase activation are not sufficient for mitogenic signaling by the hepatocyte growth factor and its truncated isoform NK2. Oncogene 18: 3399-340.
Thannickal, V.J., Bastien, M., Day, R.M., Klinz, S.G., Fanburg,B.L. (2000) Ras-dependent and independent regulation of reactive oxygen species by mitogenic growth factors and TGFb. FASEB J. 14: 1741-1748.
Rubin, J.S., Day, R.M., Breckenridge, D., Atabey, N., Taylor, W.G., Stahl, S.J., Wingfield, P.T., Kaufman, J.D., Schwall, R., Bottaro, D.P. (2001) Dissociation of heparan sulfate and receptor binding domains of hepatocyte growth factor reveals that heparan sulfate-c-Met interaction facilitates signaling. J. Biol. Chem. 276: 32977-83.
Day, R.M., Yang, Y.Z., Suzuki, Y.J., Stevens, J., Perlmutter, A., Pathi, R., Fanburg, B.L., Lanzillo, J.J. (2001) Bleomycin upregulates gene expression of angiotensin converting enzyme via MAP kinase and Egr-1 transcription factor. Am. J. Resp. Cell. Mol. Biol. 25:613-619.
Day, R.M., Bridges, B., Patel, B.K.R., Corey, S.J., Bottaro, D.P. (2002) Mitogenic complementarity between HGF-mediated PI 3-kinase activation and IL-4-mediated Stat6 activation. Oncogene 21:2201-11.
Day, R.M., Suzuki, Y.J., Lum, J.L., White, A.C., Fanburg, B.L. (2002) Bleomycin upregulates gene expression of g-glutamylcysteine synthetase in pulmonary artery endothelial cells. Am. J. Physiol. Lung Cell. Biol. 282:L1349-1357.
Thannickal, V.J., Lee, D.Y., White, E.S., Cui, Z., Larios, J.M., Horowitz, J.C., Day, R.M., Thomas, P.E. (2003) Myofibroblast differentiation by TGF-b1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J. Biol. Chem. 278:12384-12389.
Day, R.M., Thiel, G., Lum, J.M., Chevere, R.D., Yang, Y., Stevens, J., Sibert, L., Fanburg, B.L. (2004) Hepatocyte growth factor regulates angiotensin converting enzyme gene expression. J. Biol. Chem. 279:8792-8801.
Lee YH, Mungunsukh O, Tutino RL, Marquez AP, and Day RM. (2010) Angiotensin II-induced apoptosis requires SHP-2 regulation of nucleolin and Bcl-xL in primary lung endothelial cells. J Cell Sci, 123: 1634-43.
Davis TA, Landauer MR, Mog SR, Barshishat-Kupper M, Zins S, Amare MF, Day RM. (2010) Timing of captopril administration determines radiation protection or radiation sensitization in a murine model of total body irradiation. Exp Hematol, 38: 270-81.
Mungunsukh O, Lee YH, Marquez AP, Cecchi F, Bottaro DP, Day RM. (2010) A tandem repeat of a fragment of Listeria monocytogenes Internalin B protein induces cell survival and proliferation. Am J Physiol Lung Cell Biol, 299:L905-14.
Lee YH, Marquez AP, Mungunsukh O, Day RM. (2010) Hepatocyte growth factor inhibits apoptosis by the profibrotic factor angiotensin II via ERK1/2 in lung endothelial cells and lung explants. Mol Biol Cell, 21: 4240-50.
Barshishat-Kupper M, Mungunsukh O, Tipton AJ, McCart EA, Panganiban RAM, Davis TA, Landauer MR, Day RM. (2011) Captopril modulates HIF and erythropoietin responses in a murine model of total body irradiation. Exp Hematol, 39: 293-304.
Day RM, Lee YH, Han L, Kim Y-C , Feng Y-H. (2011) Angiotensin II activates AMPK for energy-dependent and -independent apoptotic signaling. Am J Physiol Lung Cell Biol, (In revision).
Panganiban, R.A., Day R.M. (2011) Hepatocyte Growth Factor in Lung Repair and Pulmonary Fibrosis (Invited review). Acta Pharmacol Sin 32: 12-20.
Day, R.M., Lee, Y.H., Han, L., Kim, Y-C., Feng, Y-H. (2011) Angiotensin II activates AMPK for energy-dependent and independent apoptotic signaling. Am J Physiol Lung Cell Biol, 301:L772-81.
Kim, Y-C., Day, R.M. (2012) Angiotensin II regulates activation of Bim via Rb/E2F1 during 1/2 and Cdk4.bapoptosis: Involvement of interaction between AMPK Am J Physiol Lung Cell Biol, in press.
Panganiban, R.A.M., Mungunsukh, O., Day, R.M. (2012) X Irradiation Induces ER Stress, Apoptosis, and Senescence in Primary Pulmonary Artery Endothelial Cells. Int J Radiat Biol, in press.