Chris Cheeseman (PhD, University of Sheffield)
7-22A Medical Science Building
University of Alberta
Canada T6G 2H7
Tel: 780 952-5875
Our main areas of interest focus on the role that facilitated hexose transporters play in health and disease. Nearly all cells use hexoses, glucose, galactose and fructose, as a major metabolic fuel and there are only two families of proteins which mediate their uptake into the cytoplasm. We work on the 14 member facilitated hexose transporter family of GLUT proteins, gene SLC2A. Our goal is to use a detailed understanding of how these proteins mediate hexose uptake to develop new analogues which could be used for cell imaging and treatment of a number of diseases including diabetes and cancer. In addition we have now shown that GLUT9 is a major transporter for urate in the kidney and we are investigating the potential role of this protein in hypertension, gout and metabolic disease.
1. Characterization of Hexose Transport in Breast Cancer.
Tumour cells have very high metabolic rates requiring them to develop a rich vascularization and express the proteins necessary to take up the substrates for their survival. Our laboratory is focusing on the expression of different GLUT proteins in breast cancer cell lines and how this affects their ability to take up different hexoses. There are 14 different GLUT proteins found in human tissues and the expression profile of many have not previously been characterized in tumours. Our goal is make use of this information combined with structure function studies (see below) to design new hexose analogues for cancer imaging and treatment.
2. Structure Function Studies of Facilitated Hexose Transport Proteins.
Little is currently known about how GLUT proteins interact at the molecular level with their different hexoses and organic anion substrates. We are using a combination of site-directed mutagenesis and computer modelling to assess the role of pore-lining amino acid residues in determining which substrates a particular GLUT protein can transport. This is key, both for a better understanding of how these proteins work, and also for the design of new molecular probes and drugs to access cells via these proteins.
3. The Role of GLUT Proteins in mediating Urate uptake and Efflux from Cells.
Humans and the great apes have very high circulating levels of urate in their plasma, which is believed to help with oxidative stress. The plasma concentration is highly regulated within narrow limits primarily by the kidney and possibly the
colon. Accumulation of uric acid within tissues leads to diseases such as gout and possibly hypertension and the recent discovery of GLUT9 as a mediator of urate movement has led us to actively investigate the role of this transporter in urate metabolism. GLUT9 is expressed in the kidney, liver and muscle and a number of single point mutations within this gene (SLC2A9) appear to correlate with hypertension and gout. Therefore, are investigating how this transporter can handle urate as well as hexoses and the effect of these SNP’s on its function.
This laboratory employs a mixture of classical physiological techniques along with molecular biology to address the specific questions outlined above. These include isolated membrane vesicle preparations, and cell culture. Molecular techniques include Western and Northern blotting, in situ hybridization, expression cloning and site-directed mutagenesis.