SOME OF OUR RUNNING RESEARCH PROGRAMMES:

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Transcriptional networks and cytoarchitecture dynamics 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. Through this program we have 

identified novel cases of transcription factors that mediate mTOR-related 

processes and cellular metabolism. We analyse their targets and how to finely 

tune their activities.

 

We complement our molecular approaches with microscopy on live and fixed samples analysing topology within cells as well as molecules' and organelles' movements in the cellular life course and within normal conditions as well as in cases where cells are stressed or phenocopy disease states.

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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 (human neuronal systems, human fibroblasts, HEK293 cells, Caco-2 cells) we investigate these interplays towards providing a knowledge platform for promoting healthy ageing.

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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. In this large research program we analyse transcriptomes, proteomes, metabolomes and genetic interactomes within cells that are resistant to mTOR inhibition and form a multi-layered network revealing the resistome of the mTOR pathway.

 

Our results will directly point towards possible vulnerabilities of resistant cells that can be further exploited in cancer biology and beyond. 

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Genetic basis of Antimycobials and Novel Antimicrobials and Antimycobials through Drug Repurposing

Resistance to antimycobials and antimicrobials is a great challenge that already affects and threatens global population health.

 

We utilise genome-wide screens using robotics and have established species agnostic analysis platforms for providing quantitative information on the genetic basis of resistance and sensitivity to stressors and drugs that affect the fitness of microbes (bacteria and yeasts).

 

We characterise current antimycobials revealing the genetics behind sensitivity and resistance. Through drug repurposing we find new antimycobials. Using gene-gene, gene-drug an drug-drug combinations we uncover novel ways of sensitising resistant strains providing solutions towards various resistomes.

 

We partner with Industry towards this, and we are open to new Industry/Academia collaborations towards healthy ageing solutions and AMR/genetic screens efforts.