Laboratory of Ann Marie Schmidt, MD
Principal Investigator
Ann Marie Schmidt, M.D.
Background for Research Focus:
The Receptor for Advanced Glycation Endproducts interacts with a range of ligands that accumulate in diverse disorders, from diabetes, tumors, immune inflammatory milieu and neurodegenerative disorders. Engagement of RAGE by these ligands activates signal transduction pathways that lead to marked alterations in cellular properties. Studies underway in our laboratory are testing the impact of genetic modification of RAGE/RAGE signaling in a wide array of RAGE-expressing cells, including endothelial cells, smooth muscle cells, monocytes, lymphocytes, neurons, podocytes and transformed cells. These studies have suggested that expression of the receptor upregulates inflammatory and tissue-destructive processes; when blocked, either by genetic approaches or pharmacological blockade, attenuation of RAGE-dependent perturbation and tissue injury results.
Main Focus of the Laboratory:
Our laboratory has established multiple techniques, both in animal models and tissue culture, to dissect RAGE signaling, the elements that control transcriptional regulation of the receptor, and the pathogenesis of complications of disorders in which the ligands accumulate. Strategies include the generation of RAGE-modified mice and novel antagonists (in collaboration with pharmaceutical partners). Our goal is to “translate” our findings from the laboratory into early phase clinical trials and testing of novel antagonists of the receptor in human subjects. Collaborators that span the basic to the clinical sciences have been assembled to accomplish these goals.
Current Projects:
As summarized above
Recent Publications:
Wendt, T.M., Tanji, N., Guo, J., Kislinger, T.R., Qu, W., Lu, Y., Bucciarelli, L.G., Rong, L.L., Moser, B., Markowitz, G.S., Stein, G., Bierhaus, A., Liliensiek, B., Arnold, B., Nawroth, P.P., Stern, D.M., D’Agati, V.D., and Schmidt, A.M. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. American Journal of Pathology 162:1123-1137, 2003.
Sakaguchi T., Yan, S.F., Yan, S.D., Rong, L.L., Sousa, M., Belov, D., Andrassy, M., Marso, S.P., Duda, S., Arnold, B., Liliensiek, B., Nawroth, P.P., Stern, D.M., Schmidt, A.M., and Naka, Y. Arterial restenosis: central role of RAGE-dependent neointimal expansion. Journal of Clinical Investigation 111:959-972, 2003.
Zhou, Z., Wang, K., Penn, M.S., Marso, S.P., Lauer, M.A., Forudi, F., Zhou, X., Qu, W., Lu, Y., Stern, D.M., Schmidt, A.M., Lincoff, A.M., and Topol, E.J. Receptor for AGE (RAGE) mediates neointimal formation in response to arterial injury. Circulation: 107:2238-2243, 2003.
Lalla, E., Lamster, I.B., Hofmann, M.A., Bucciarelli, L.G., Jerud, A.P., Tucker, S., Lu, Y., Papapanou, P.N., and Schmidt, A.M. Oral infection with a periodontal pathogen accelerates atherosclerosis in apolipoprotein E null mice. Arteriosclerosis, Thrombosis and Vascular Biology 23:1405-1411, 2003.
Cipollone, F., Iezzi, A., Fazia, M., Zucchelli, M., Pini, B., Cuccurullo, C., De Cesare, De Blasis, G., Murano, R., Bei, R., Chiarelli, F., Schmidt, A.M., Cuccurullo, F., and Mezzetti, A. The Receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control. Circulation 108:1070-1077, 2003.
Harja, E., Bucciarelli, L.G., Lu, Y., Stern, D.M., Zou, Y.S., Schmidt, A.M., and Yan, S.F. Early growth response-1 promotes atherogenesis: mice deficient in early growth response-1 and apolipoprotein E display decreased atherosclerosis and vascular inflammation. Circulation Research 94:333-339, 2004.
Zeng, S., Feirt, N., Goldstein, M., Guarrera, J., Ippagunta, N., Ekong, U., Dun, H., Lu, Y., Qu, W., Schmidt, A.M., and Emond, J.C. Blockade of receptor for advanced glycation end products (RAGE) attenuates ischemia and reperfusion injury to the liver in mice. Hepatology 39:422-432, 2004.
Hwang, Y.C., Kaneko, M., Bakr, S., Liao, H., Lu,Y., Lewis, E.R., Yan, S.D., Ii, S., Itakura, M., Rui, L., Skopicki, H., Homma, S., Schmidt, A.M., Oates, P.J., Szabolcs, M., and Ramasamy, R. Central role for aldose reductase pathway in myocardial ischemic injury. In press, FASEB Journal, 2004.
Hudson, B.I., Bucciarelli, L.G., Wendt, T., Sakaguchi, T., Lalla, E., Qu, W., Lu, Y., Lee, L., Stern, D.M., Naka, Y., Ramasamy, R., Yan, S.D., Yan, S.F., D’Agati, V., and Schmidt, A.M. Blockade of receptor for advanced glycation endproducts: a new target for therapeutic intervention in diabetic complications and inflammatory disorders. Archives of Biochemistry and Biophysics 419:80-88, 2003.
Yan, S.F., Ramasamy, R., Naka, Y., and Schmidt, A.M. Glycation, Inflammation and RAGE: A scaffold for the macrovascular complications of diabetes and beyond. Circulation Research 93:1159-1169, 2003.
Recent (last 5 years) Surgery Residents (Columbia and outside):
Surgical residents have collaborated with our group over the past five years, including Juliet Park, Patricia Sylla, Taichi Sakaguchi and, Michael Goldstein.
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