The kinase TOR is a key regulator of cell growth and organismal metabolism in animals. Consequently, the correct regulation of TOR activity is important both for normal development and for disease. For instance, TOR is hyperactivated in almost all human cancers, and reduced TOR activity is associated with leanness and resistance to obesity. TOR activity is regulated by a number of inputs including, importantly, amino acids. Indeed, nutritional amino-acid overload in humans is thought to promote insulin resistance via TOR activation. However, the molecular mechanism by which amino acids regulate TOR is still mysterious. I propose here to identify and characterize factors required for amino acids to regulate TOR. We will use a genome-wide functional-genomics approach to systematically identify a large number of genes involved in this process, thereby hopefully making a significant contribution to the field. Identification of these novel factors may open avenues for diagnosis and treatment of cancer and metabolic disease. This project will exploit a high-throughput, cell-based screen for genes involved specifically in amino acid sensing by TOR which we have implemented in my lab. In collaboration with the neighbouring Boutros lab, we have performed a pilot screen on the 780 kinases of the human genome, proving that the screen is working successfully, and yielding a number of interesting hits which we have validated. The PhD student in my lab who performed the pilot screen is now characterizing these new genes. I would like to fully exploit this platform by executing the screen on a genome-wide level, and following-up on the genes that will be discovered. However, I do not have the necessary resources to do so. An ERC starting grant would allow us to do this, leveraging our technology platform and the work we invested in creating it. I strongly believe these results will be exciting and of general interest, helping to establish me in the field.
Start Date: 01.09.2010 End Date: 31.08.2015 EU Contribution: 1.5 Mio Euro Total Costs: 1.5 Mio Euro Funding Scheme: ERC Starting Grant 2010