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PROJECT DESCRIPTION

AMPKIN is a project supported within the Sixth Framework Programme of the European Commission. The project period is three years strating from January 1, 2006.

In this project experimental and theoretical studies will be integrated to achieve a better understanding of the dynamic operation of the AMP-activated protein kinase (AMPK) signalling pathway. This pathway plays a central role in monitoring the cellular energy status and controlling energy production and consumption. The conceptional project idea is to generate mathematical descriptions of pathway activation/deactivation in yeast and mammalian cells. The computational models will support drug development in an industrial context. If successful, the results will have major payoff to tackle some of the most rapidly advancing diseases in the modern world, obesity and type-2 diabetes. The project will result in a case study for employing systems biology in drug target identification and in drug development.

AMPK is the sensor of the cellular energy status. The organisation, function and physiological roles of the AMPK pathway are highly conserved from yeast to human. AMPK/SNF1 pathways

The detailed molecular mechanisms that control AMPK are still incompletely understood.

The central cellular function of AMPK is to switch off ATP consuming processes and to stimulate ATP-production. AMPK also seems to have roles in the control of whole-body energy homeostasis. In yeast AMPK/Snf1 is best known for its role in glucose repression/ derepression.

The number of "new molecular entities" submitted to regulatory authorities for registration as therapeutic agents has steadily decreased and most large pharmaceutical companies, as well as the companies in the biotech sector, have disappointingly thin drug development pipelines. It appears that an inability to translate genome information into an understanding of biological complexity hampers the development of novel therapies. For this reason, early drug discovery stages will benefit by placing target molecules and their chemical modulators into a meaningful biological context by systems biology approaches. We also believe that our systems biology approach will have an impact on development of new disease diagnosis tools and predictions of disease progression, by the holistic understanding of different genetic- and chemical factors influence on AMPK-dependent energy metabolism"

The overall objective of this project is to generate mathematical models of the AMPK pathway that will then be used in drug target identification and drug screening. In this sense, the project will deliver a case study for integration of data and models from different organisms for the use of systems biology in drug development. In addition, the project is expected to deliver substantial new knowledge on the function, operation and physiological roles of AMPK in yeast and mammalian cells, new tools for experimental research such as in microscopy and bioimaging and improved software tools for systems biology.