Lucille P. Markey Charitable Trust

sponsor of

Basic and Clinical Research Career Tracks in Internal Medicine at

Columbia-Presbyterian Medical Center

Research Interests

Research Activities

Dr. Andrew Marks' research has contributed fundamental insights into the molecular mechanisms regulating contraction of normal and failing cardiac muscle, molecular triggers of cardiac arrhythmias and coronary artery in-stent restenosis. His discoveries have led to promising new therapies for these diseases. He showed that the calcium release channel of the sarcoplasmic reticulum (SR) is a macromolecular complex containing the ryanodine receptor/calcium release channel (RyR), FKBP12/12.6 (calstabin), PKA, PP1, PP2A, and their targeting proteins. He discovered a mechanism that contributes to cardiac dysfunction in failing hearts: RyR PKA hyperphosphorylation that causes "leaky" channels that can deplete SR calcium contributing to decreased muscle contractility, and can trigger fatal cardiac arrhythmias. He showed a molecular mechanism for the beneficial effects of beta adrenergic receptor blockers in heart failure. In addition, Marks has demonstrated the essential role of the IP3 receptor/calcium release channel and its modulation by Fyn tyrosine kinase phosphorylation in T-cell receptor signaling and in some forms of apoptotic signaling. Dr. Marks' discovery of the molecular mechanisms underlying the anti-proliferative and anti-migratory effects of rapamycin on vascular smooth muscle cells (VSMC) contributed to development of drug eluting stents. Using rapamycin-resistant cells, developed in his laboratory, he demonstrated that the drug inhibits VSMC cell cycle progression by elevating cyclin-dependent kinase inhibitor p27. In summary, Marks' pioneering work in molecular cardiology, vascular biology has catalyzed substantive progress in cardiovascular biology and therapeutics. As Editor-in-Chief of the Journal of Clinical Investigation Marks has helped maintain and develop this vibrant forum for biomedical research and has introduced features including Science in Medicine and Society and Science that address the links between fundamental biomedical research, science policy and the development of novel therapeutics that benefit patients

Selected Publications

Jayaraman, T., Brillantes, A.-M., Timerman, A.P., Fleischer, S., Erdjument-Bromage, H, Tempst, P and Marks, A.R. (1992) FK-506 Binding Protein Associated with the Calcium Release Channel (Ryanodine Receptor) J. Biol. Chem 267: 9474-9477.

Jayaraman, T., and Marks, AR (1993) Rapamycin-FKBP12 blocks proliferation induces differentiation and inhibits cdc2 kinase activity in a myogenic cell line J. Biol. Chem. 268: 25385-25388.

Brillantes, A-M. B., Ondrias, K., Scott, A., Kobrinsky, E., Ondriasova, E, Jayaraman, T., Moschella, MC, Landers, M., Ehrlich, B.E., and Marks, A.R. (1994) Stabilization of calcium release channel (ryanodine receptor) function by FK-506 binding protein Cell 77: 513-523.

Jayaraman, T, Ondriasova, E., Ondrias, K., Harnick. D., and Marks, A.R. (1995) The inositol 1,4,5-trisphosphate receptor is essential for T cell receptor signaling Proc. Natl. Acad. Sci. 92:6007-6011.

Jayaraman, T., Ondrias, K., Ondriasova, E., and Marks, A.R. (1996) Regulation of the Inositol 1,4,5-Trisphosphate Receptor by Tyrosine Phosphorylation Science 272: 1492-1494.

Poon, M., Marx, S.O., Gallo, R., Badimon, J.J., Taubman, M.B. and Marks, A.R. (1996) Rapamycin inhibits vascular smooth muscle cell migration J. Clin. Invest. 98:2277-2283.

Luo, Y., Marx, S., Koff, A., Massague, J., and Marks, A.R. (1996) Rapamycin Resistance Tied To Defective Regulation of p27kip1 Mol. Cell. Biol. 16:6744-6751.

Marx, S.O., Ondrias, K., and Marks, A.R. (1998) Coupled gating between individual skeletal muscle ryanodine receptor/calcium release channels Science 281:818-821.

Marx, S.O., Reiken, S., Hisamatsu, Y., Jayaraman, T., Burkhoff, D., Rosemblit, N., and Marks A.R., (2000) PKA Phosphorylation Dissociates FKBP12.6 from the Calcium Release Channel (Ryanodine Receptor): Defective Regulation in Failing Hearts Cell 101:365-376.

Marx, S.O., Reiken, S., Hisamatsu, Y., Gaburjakova, M., Gaburjakova, J., Yang, Y.-M., Rosemblit, N., and Marks, A.R., (2001) Phosphorylation-dependent Regulation of Ryanodine Receptors: A Novel Role for Leucine/Isoleucine Zippers J. Cell Biol. 153:699-708.

Marx, S.O., Kurokawa, J. Reiken, S., Motoike, H., D'Armiento, J., Marks, A.R., Kass, R. (2002) Beta-adrenergic receptor modulation of the KCNQ1/KCNE1 potassium channel requires a macromolecular signaling complex Science 295:496-499.

Wehrens, X., Lehnart, S.E., Reiken, S.R., Vest, J., Mohler, P., Huang, F., Guatimosim, S., Rosemblit, N., Napolitano, C., Memmi, M., Priori, S.G., Lederer, W.J., Marks, A.R. (2003) FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death Cell 113:829-840.