Transcriptional networks in ageing and neurodegeneration

Using 2D/3D human neuronal cultures as well as genetic approaches in the fruitfly

Drosophila melanogaster we analyze gene and protein networks in normal and

pathological conditions during TOR-active and inactive states.

We use transcriptomics and proteomics and data integrations

towards elucidating the role of TOR in neurodegeneration and identifying molecular

markers, players and targets for interventions.

Integrating cellular space and time in physiology, disease and ageing

The connections between nutrient availability, TOR and length of life have been studied intensively. These studies have shown that TOR controls the amount as well as the quality of the proteins produced within cells together with the recycling of biological material (a process that is known as 'autophagy'). High amounts of protein production and reduction in the recycling quality are detrimental. We and others have found such physical and genetic connections and have provided additional potential targets for drug development against age-related diseases. However, the connections and workings between cellular space and lifespan are not well understood. Using fission yeast and mammalian tissue culture systems we investigate these interplays towards providing a knowledge platform for promoting healthy ageing.

Mechanisms of uncoupling cellular growth from nutrient availability and mTOR pathway activity

Inhibition of TOR through genetic or pharmacological means has a profound negative effect on cell growth. Mutated and overactivated TOR pathway is directly implicated in many cancers and numerous clinical trials are currently ongoing. However, cells (including cancer cells) are able to rewire their metabolism and resume growth in states where TOR is inhibited. This phenomenon shows that there are mechanisms of bypassing the requirements of TOR for growth and, essentially, uncouple nutrient and growth factor availability from cell division. Nevertheless, these mechanisms are not well understood. By utilising multi-omics and network biology we start revealing a comprehensive genetic connectivity roadmap of the molecular mechanisms involved in this TOR-resistance phenomena. Our results will directly point towards possible vulnerabilities of resistant cells that can be further exploited in cancer biology and beyond.