Transcriptional networks in ageing and neurodegeneration

In this project we use 2D/3D human neuronal cultures and Drosophila to 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 showed that TOR controls the amount and quality of proteins produced within the cells as well as how materials are recycled (a process known as 'autophagy'). More protein production and less effective recycling are detrimental. We and others have found such connections and have provided additional potential targets for drug development against age-related diseases. However, the connections and workings between cell space and lifespan are not well understood. This research programme we will shed light into this and provide 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 implicated in many cancers and numerous clinical trials are currently ongoing. However, cells (including cancer cells) can rewire their metabolism and resume growth in states where TOR is inhibited. This shows that there are mechanisms of bypassing the requirement of TOR for growth and essentially uncoupling nutrient and growth factor availability from cell division. Nevertheless, these mechanisms have remained elusive. In this project, we will utilise multi-omics and network biology and will provide a comprehensive genetic connectivity roadmap that will reveal the molecular mechanisms that are involved in inhibition of TOR resistance. Our results will directly point towards possible vulnerabilities of resistant cells that can be further exploited in cancer biology and beyond.