Research objectives and content
Progression through the cell-cycle is regulated at key checkpoints by a rise in cytosolic calcium. Abnormalities in calcium signalling can give rise to uncontrolled cell growth, resulting in cancer. In non-excitable cells, calcium can be elevated either by release from IP3-sensitive intracellular pools or through the store-operated calcium entry pathway (ICRAC)- However, the properties of both calcium release and ICRAC during different stages of the cell-cycle have not been investigated. Using electrophysiological (patch-clamp) and optical techniques (calcium imaging) experiments therefore will be designed to address how calcium release and entry change during the cell-cycle. ICRAC is extensively regulated by cytosolic processes, and the cell-cycle dependence of this regulation will be investigated. Finally, experiments will be carried out to examine the cell-cycle-dependent expression of potassium channels, since these channels maintain a large electrical driving force for calcium influx. Elucidation of these processes is important not only for a more complete understanding of cell-cycle events, but also opens up new areas for pharmacological treatment of human diseases like certain cancers. Training content (objective, benefit and expected impact)
During my stay in Oxford I will learn the powerful method of high resolution digital calcium imaging which will be of fundamental benefit in my future research. I will also focus extensively on ICRAC, and will gain invaluable experience in measuring this important, but small, calcium current. Dr. Parekh's lab. is one of the few in europe that is technically able to reliably measure this current, and he has much experience in the ICRAC field, having worked on it for several years. I also will learn to combine measurements of ICRAC simulataneously with calcium imaging of the intracellular calcium stores. This is a state-of-the-art method which will be of significant importance in enhancing our understanding of the interaction between calcium release and calcium influx.
Links with industry / industrial relevance (22)
In the future, I would like to continue my pharmaceutical work (which began when I was a student) and interact closely with industry. A specific inhibitor of ICRAC has not been designed or isolated yet. Because of the technical skills required to measure ICRAC, direct assays of drugs are not carried out. Once I have become an expert in measuring ICRAC, I would like to help develop specific inhibitors of the current which will be of major clinical relevance.