- B.S., University of Regensburg, 1991
- M.S., University of Regensburg, 1993
- Ph.D., University of Regensburg, 1997
- Post-doc, University of Regensburg, 1997-98
- Post-doc, Mayo Clinic Scottsdale, AZ, 1998-01
- Research Associate, Mayo Clinic, 2001-05
- Cystic Fibrosis Foundation
Cystic fibrosis is a disease of defective epithelial salt and fluid transport that is caused by mutations in CFTR (cystic fibrosis transmembrane conductance regulator). A major focus of my research is the biosynthetic processing and intracellular trafficking of CFTR. This multi-domain protein functions as a chloride channel in apical membranes of epithelial cells and in addition regulates other ion channels and transporters. More than 1500 different mutations in the CFTR gene have been identified in cystic fibrosis patients, however, a deletion of phenylalanine 508 (DF508) is most common and present in more than 90% of cystic fibrosis patients. The misfolded protein DF508 cannot mature conformationally and is recognized by ER quality control and therefore is not able to proceed to Golgi and plasma membrane. Growth of cells at reduced temperature or other manipulations enable the nascent mutant protein to avoid ER quality control and reach the cell surface, but it is rapidly cleared from the distal secretory pathway and degraded in lysosomes. Rescue of DF508 CFTR from ER retention is currently being intensively pursued as a potential therapeutic approach to alleviate cystic fibrosis disease. Our lab has a specific interest in the endocytic trafficking of rescued DF508 CFTR and we have recently found that rescue of the mutant protein from ER retention by some means affects endocytic routing of other components e.g. cholesterol and glycosphingolipids.
The long-term goal of the laboratory is to investigate means of rescuing cell surface expression of DF508 CFTR, while still retaining normal endocytic trafficking.
To study intracellular trafficking, we employ multiple modern research approaches such as molecular and cellular biology techniques, protein and lipid biochemistry, confocal and live cell microscopy, primary and passaged highly differentiated human airway epithelial cultures and viral vectors for gene transfer.
We are currently working on the following projects:
- Intracellular trafficking of rescued DF508 CFTR.
- Consequence of DF508 CFTR rescue on endocytic protein and lipid traffic.
- Redirection of chloride channels ClC-3A and 3B to compensate for CFTR in cystic fibrosis.
- Gentzsch, M., Choudhury, A. Chang, X.B., Pagano, R., Riordan, J.R. (2007) Missambled mutant DF508 CFTR in the distal secretory pathway alters cellular lipid trafficking. J. Cell Sci. 120: 447-455.
- Thelin, W.R., Chen, Y., Gentzsch, M., Kreda,S., Sallee, J., Scarlett, C., Borchers, C., Jacobson, K., Stutts, K.J., Milgram, S. (2007) A direct interaction with filamins modulates the stability and plasma membrane expression of CFTR. J. Clin. Invest. 117: 364-374.
- Cui, L., Aleksandrov, L., Chang, X.B., Hou, Y.X., He, L., Hegedus, T.,Gentzsch, M., Aleksandrov, A., Balch, W.E. and Riordan, J.R. (2007) Domain interdependence in the biosynthetic assembly of CFTR. J. Mol. Biol. 365: 981-994.
- Hegedus, T., Aleksandrov, A., Cui L., Gentzsch, M., Chang, X.B. and Riordan, J.R. (2006) DF508 CFTR with two altered RXR motifs escapes from ER quality control but its channel activity is thermally sensitive. Biochim. Biophys. Acta.:1758: 565-72.
- Cui, L., Aleksandrov, L., Hou, Y.X., Gentzsch, M., Chen, J.H., Riordan, J.R. and Aleksandrov, A. (2006) The role of cystic fibrosis transmembrane conductance regulator phenylalanine 508 side chain in ion channel gating. J Physiol. 572: 347-58.
- Grubb, B.R., Gabriel, S.E., Mengos, A., Gentzsch, M., Randell, S.H., Van Heeckeren, A.M., Knowles, M.R., Drumm, M.L., Riordan, J.R., Boucher, R.C. (2005) SERCA Pump Inhibitors Do Not Correct Biosynthetic Arrest of DF508 CFTR in Cystic Fibrosis. Am. J. Respir. Cell. Mol. Biol. 34: 355-363.
- Gentzsch, M., Chang, X.B., Cui, L., Wu, Y., Ozols, V.V.,Choudhury, A.K., Pagano, R.E. and Riordan, J.R. (2004) Endocytic trafficking routes of wild-type and DF508 CFTR. Mol. Biol. Cell. 15: 2684-2696.
- Malmberg, E.K., Andersson, C.X., Gentzsch, M., Chen, J.H., Cui, L., Hansson, G.C. and Riordan, J.R. (2004) Bcr (breakpoint cluster region) protein binds to PDZ-domains of scaffold protein PDZK1 and vesicle coat protein Mint3. J. Cell Sci. 117: 5535-5541.
- Gentzsch, M., Cui, L., Mengos, A., Chang, X.B., Chen, J.H. and Riordan, J.R. (2003) The PDZ-binding Chloride Channel ClC-3B localizes to the Golgi and associates with Cystic Fibrosis Transmembrane Conductance Regulator-interacting PDZ Proteins. J. Biol. Chem. 278: 6440-6449.
- Gentzsch, M., Aleksandrov, A., Aleksandrov, L. and Riordan J.R. (2002) Functional analysis of the C-terminal boundary of the second nucleotide binding domain of the cystic fibrosis transmembrane conductance regulator and structural implications. Biochem J. 366: 541-548.
- Gentzsch, M. and Riordan J.R. (2001) Localization of sequences within the C-terminal domain of the cystic fibrosis transmembrane conductance regulator which impact maturation and stability. J. Biol. Chem. 276: 1291-1298.