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Jorge Fischbarg, M.D., PH.D.
Professor Emeritus of Physiology and Cellular Biophysics
Email: jf20@columbia.edu
Tel: (212) 305-9092
Office:Eye Institute, 612
Fax: (212) 305-2461


CURRENT RESEARCH

MOLECULAR BIOPHYSICS OF CELL MEMBRANE TRANSPORTERS AND WATER CHANNELS; VOLUME REGULATION.

Dr. Fischbarg's laboratory is interested in the mechanism by which water is transported across epithelial layers such as those in the cornea and other organs of the eye. These mechanisms are crucial for ocular functions such as maintaining corneal transparency and normal intraocular pressure. Work is done at the cellular and molecular levels. Cellular studies include how volume regulation and cell signaling is related to fluid transport. Other studies deal with proteins relevant to such mechanisms, such as water channels, cotransporters and glucose transporters; these studies include expression of these proteins in amphibian oocytes, mutagenesis, molecular modeling, and modeling of the biophysical mechanism by which water transfer is coupled to electrolyte transport across epithelial layers.

Several proteins of our interest have been cloned in recent years, and provide high-conductance, specific paths for water. Other membrane proteins provide lower conductance but still meaningful paths for water, such as the glucose transporter, whose water conductance was first determined in our laboratory. Typical questions we ask are: How do protein water channels fit into the fluid transport mechanism? What are the topological and structural features that underlie water channel function? What is the number of molecules occupying a water channel pore? Are these channels subject to modulation? If cells are devoid of water channels, do other membrane proteins provide aqueous pathways through the membrane? What is the water conductance of transporters of small and large substrates? Are transporters simply a particular case of gated channels? What are the three-dimensional structures of the different classes of membrane proteins? Can they be crystallized? To study these problems, we utilize a variety of tissues and techniques. We determine osmotic permeability of cells from transient changes in the intensity of light scattered by cultured cells in response to osmotic challenge. We also express native and mutant water channels, glucose transporters and other membrane proteins in amphibian oocytes to examine their functions, especially their water conductance. We study molecular models based on the known sequences and crystallographic information for water channels and glucose transporters; such modeling directs the mutations we do in individual residues. We work on the theory of water permeation across single-file pores, and we conduct computer dynamics simulations of water permeation across water channels. Given the ubiquitous presence of water, these questions are basic and fundamental; answers to them may open new physiological insights, and new therapeutic approaches.


SELECTED PUBLICATIONS

Manolescu, A., Salas-Burgos, A.M., Fischbarg, J., and Cheeseman, C.I. 2005. Identification of a hydrophobic residue as a key determinant of fructose transport by the facilitative hexose transporter SLC2A7(GLUT7). J Biol Chem. 280(52):42978-83.

Diecke, F.P., Wen, Q., Iserovich, P., Li, J., Kuang, K., and Fischbarg, J. 2005. Regulation of Na-K-2Cl cotransport in cultured bovine corneal endothelial cells. Exp Eye Res. 80:777-85.

Uhlemann, A.C., Cameron, A., Eckstein-Ludwig, U., Fischbarg, J., Iserovich, P., Zuniga, F.A., East, M., Lee, A., Brady, L., Haynes, R.K., and Krishna, S. 2005. A single amino acid residue can determine the sensitivity of SERCAs to artemisinins. Nat Struct Mol Biol. 12:628-9.

Fischbarg, J., and Diecke, F.P. 2005. A mathematical model of electrolyte and fluid transport across corneal endothelium. J Membr Biol. 203:41-56.

Rodriguez ,P., Rivas, C.I., Godoy, A., Villanueva, M., Fischbarg, J., Vera, J.C., and Reyes, A.M. 2005. Redefining the facilitated transport of mannose in human cells: absence of a glucose-insensitive, high-affinity facilitated mannose transport system. Biochemistry. 44:313-20.

Salas-Burgos, A., Iserovich, P., Zuniga, F., Vera, J.C., Fischbarg, J. 2004. Predicting the three-dimensional structure of the human facilitative glucose transporter glut1 by a novel evolutionary homology strategy: insights on the molecular mechanism of substrate migration, and binding sites for glucose and inhibitory molecules. Biophys J. 87:2990-9.

Kuang, K., Li, Y., Yiming, M., Sanchez, J.M., Iserovich, P., Cragoe, E.J., Diecke, F.P., and Fischbarg, J. 2004. Intracellular [Na+], Na+ pathways, and fluid transport in cultured bovine corneal endothelial cells. Exp Eye Res. 79:93-103.

Fischbarg, J., Maurice, D.M. 2004. An update on corneal hydration control. Exp Eye Res. 78:537-41.

Kuang, K., Yiming, M., Wen, Q., Li, Y., Ma, L., Iserovich, P., Verkman, A.S., and Fischbarg, J. 2004. Fluid transport across cultured layers of corneal endothelium from aquaporin-1 null mice. Exp Eye Res. 78:791-8.

Diecke, F.P., Wen, Q., Sanchez, J.M., Kuang, K., and Fischbarg, J. (2004). Immunocytochemical localization of Na+-HCO3- cotransporters and carbonic anhydrase dependence of fluid transport in corneal endothelial cells. Am J Physiol Cell Physiol. 286:C1434-42.

Joet, T., Morin, C., Fischbarg, J., Louw, AI, Eckstein-Ludwig, U., Woodrow, C., and Krishna, S. 2003. Why is the Plasmodium falciparum hexose transporter a promising new drug target? Expert Opin Ther Targets. 7:593-602.

Wang, D., Pascual, J.M., Iserovich, P., Yang, H., Ma, L., Kuang, K., Zuniga, F.A., Sun, R.P., Swaroop, K.M., Fischbarg, J., and De Vivo, D.C. 2003. Functional studies of threonine 310 mutations in Glut1: T310I is pathogenic, causing Glut1 deficiency. J Biol Chem. 278:49015-21.

Iserovich, P., Yiming, M., Wang, Z., Bildin, V.N., Reinach, P.S., and Fischbarg, J. 2002. Epidermal growth factor stimulates fluid transport in SV40 transformed rabbit lacrimal gland cells. Adv Exp Med Biol. 506(Pt A):243-7. Klepper J, Florcken A, Fischbarg J, Voit T. (2003). Effects of anticonvulsants on GLUT1-mediated glucose transport in GLUT1 deficiency syndrome in vitro. Eur J Pediatr. 162:84-9.

Reyes, A.M., Bustamante, F., Rivas, C.I., Ortega, M., Donnet, C., Rossi, J.P., Fischbarg, J., and Vera, J.C. 2002. Nicotinamide is not a substrate of the facilitative hexose transporter GLUT1. Biochemistry. 41:8075-81.

Manning, S.K., Woodrow, C., Zuniga, F.A., Iserovich, P., Fischbarg, J., Louw, A.I., and Krishna, S. 2002. Mutational analysis of the hexose transporter of Plasmodium falciparum and development of a three-dimensional model. J Biol Chem. 277:30942-9.

Iserovich, P., Wang, D., Ma, L., Yang H, Zuniga F.A., Pascual, J.M., Kuang, K., De Vivo, DC., and Fischbarg, J. 2002. Changes in glucose transport and water permeability resulting from the T310I pathogenic mutation in Glut1 are consistent with two transport channels per monomer. J Biol Chem. 277:30991-7.

Fischbarg J. 1997. The mechanism of fluid transport across corneal endothelium and other epithelial layers: A possible explanation based on cyclic cell volume regulatory changes. Brit. J. Ophthalmol., 81:1-5.

Fischbarg, J., Kuang, K., Li, J., Iserovich, P., and Wen, Q. 1997. Aquaporins and ion conductance. Science, 275, 1492.

Loike, J.D., Hickman, S., Kuang, K., Xu, M., Cao, L., Vera, J.C., Silverstein, S.C., and Fischbarg, J. 1996. Sodium/glucose cotransporters display sodium and phlorizin-dependent water permeability. Am. J. Physiol., 271:C1774-1779.

Vera, J.C., Rivas, C.I., Fischbarg, J, and Golde, D.W. 1993. Mammalian Facilitative Hexose Transporters Mediate the Transport of Dehydroascorbic Acid. Nature, 364:79-82.

Echevarría, M., Kuang, K., Iserovich, P., Li, J., Preston G.M., Agre, P., and Fischbarg, J. 1993. Cultured bovine corneal endothelial cells express CHIP28 water channels. Am. J. Physiol., 265, CP34, (Cell Biol, 34) C1349-C1355.


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