Dr. Larry Fliegel
Research in Dr. Fliegel’s laboratory investigates membrane proteins function, how intracellular pH is regulated and the role of Na+/H+ exchanger in human disease, especially heart disease and breast cancer. The work is funded by CIHR and other sources. Dr. Fliegel has published over 150 publications in numerous journals including J. Biological Chemistry, J. Molecular and Cellular Cardiology, Hypertension, Cancer Research, Basic Research in Cardiology and others. He has authored two books and served on several editorial boards of Journals and grant panels such as CIHR. His awards include a Killam Annual Professor Award (2009-10), a Tier one Basic Science Mentoring Award (2013), McCalla Research Professorship Award (2007) and Alberta Heritage Foundation for Medical Research Scientist Award (2006-2013).
Specific Research Projects
A. As a result of metabolism, excess intracellular acid is produced in all cells. The mammalian Na+/H+ exchanger isoform 1 (NHE1) is a ubiquitously expressed membrane protein which deals with this problem. In higher eukaryotes this integral membrane protein functions to remove one intracellular H+ for one extracellular Na+. We have a special interest in the Na+/H+ exchanger in the mammalian heart, because the protein is important in heart disease. In the heart we have examined regulation of expression and activity of the protein. We have shown that MAP kinase dependent pathways are key to the regulation of activity of the Na+/H+ exchanger. Studies are underway to examine these and new key regulators of the protein in the heart.
B. The Fliegel laboratory is also interested in studies on the fundamental nature of the Na+/H+ exchanger protein with the aim being to understand its mechanism of transport, including its structure. The aim of one project is to essentially reconstruct the human protein from its parts and from biochemical data, determining its structure and its mechanism of transport. This is being accomplished by a combination of techniques including site specific mutagenesis of the protein, cysteine scanning and accessibilities studies, production of the protein in E. coli and analysis of the structure of regions of the protein by nuclear magnetic resonance. These results will lead to important fundamental contributions to the analysis of ion transport through membranes and may lead to the design of improved inhibitors for clinical treatment.
C. Another area that is being studied is the regulation of the Na+/H+ exchanger in breast cancer. Activity of this protein is elevated in breast cancer and this elevated activity is a triggering factor in metastasis, which is the leading cause of fatality in breast cancer. This area of research involves identification of the key factors triggering elevated NHE1 activity in the disease. It examines which regulatory pathways and regulatory proteins are ultimately responsible for the resulting metastasis. It is hoped that identifying these pathways will lead to new strategies to suppress activity, and the resulting metastasis.
D. We also have a great interest in pH regulation and ion movements in plants and yeast. In Schizosaccharomyces pombe the yeast Na+/H+ exchanger (sod2) moves Na+ out of the cell in exchange for H+. In plants the yeast equivalent, SOS1 does the same thing making some plants resistant to salt containing water. We have examined amino acids important in cation binding and transport in this protein. Our long-term goal is to understand how ions and coordinated and transported in membrane proteins and discover how salt tolerance in plants functions.
The laboratory continues to be involved in new and exciting studies on regulation of activity and expression of Na+/H+ exchange proteins and diseases in humans. Many new projects are underway. We are always interested in recruiting high quality personnel so please contact me if you are interested in this area.
Our laboratory studies the regulation of intracellular pH and the removal of excess intracellular acid. In mammalian tissues the main protein responsible for this is the Na+/H+ exchanger.
Dr. Larry Fliegel
Associate Chair, Department of Biochemistry
Ph.D., University of Calgary
Department of Biochemistry
Faculty of Medicine & Dentistry
University of Alberta
347 Medical Sciences Building
Edmonton, Alberta, Canada T6G 2H7
Lab Tel: 780.492.1847