Due to its role as a primary hub in metabolic and nutrient signalling, and a key regulator of virtually all cellular functions, most of our projects centre around the master cellular nutrient sensor and growth coordinator, the mTOR kinase; and its main negative upstream regulator, the tumour suppressor TSC (Tuberous Sclerosis) protein complex. Furthermore, given the central function of mTOR in the ageing process—and that dysregulation of the nutrient sensing machinery is a hallmark of ageing—our research investigates fundamental aspects of healthy ageing and age-related diseases.
To achieve this, we combine high-throughput omics approaches (functional genomic screens, proteomics, metabolomics, interactome/proximome analyses) with state-of-the-art molecular biology, biochemistry, cell biology, gene-editing, and high-resolution microscopy techniques. We make use of established human and mouse cell lines, cancer cell lines, patient-derived cells, as well as model organisms (together with our collaborators), to identify evolutionarily conserved processes and to address multiple fundamental questions. Overall, our vision is to understand: i) how mammalian cells sense the availability of nutrients and the presence of stresses in their environment to adjust their metabolism, growth, and other functions accordingly, ii) how the dysregulation of these cellular mechanisms contributes to the development of human diseases and to the ageing process, and iii) how we can intervene—pharmacologically or nutritionally—to efficiently and specifically target such life-threatening conditions.
The ability of cells to sense and respond to nutrients is a foundational principle of life. Every organism, from single-celled yeast to humans, relies on this process to adapt growth and metabolism to environmental conditions. At the core of this regulation is mTORC1, a master signaling hub that integrates nutrient availability with nearly every aspect of cell biology.
Importantly, dysregulation of mTORC1 activity and of nutrient sensing is a common thread linking diverse human diseases: For instance, cancer cells often hijack mTORC1 to fuel uncontrolled growth and proliferation. In metabolic diseases such as type 2 diabetes and obesity, mTORC1 contributes to disrupted nutrient sensing and impaired insulin signalling. In neurodegenerative diseases such as Alzheimer’s, aberrant mTORC1 activity interferes with cellular recycling and protein homeostasis. Finally, in ageing, hyperactivation of mTORC1 accelerates functional decline across tissues. Because mTORC1 touches so many aspects of human biology, insights into its (de)regulation have unusually broad potential for improving health.
Despite the central importance of mTORC1 for cellular physiology in health, disease, and ageing, our current understanding of how it operates is incomplete. Therefore, the primary and immediate focus of our research is to uncover the principles by which mTORC1 activity is regulated by nutrients in time and space inside cells, and to identify novel regulators, effectors, and points of intervention. This knowledge opens up entirely new lines of investigation in nutrient signaling. The societal impact of or work represents the mid- to long-term opportunities that can be seized once these cellular mechanisms are better understood. In other words, our work generates the foundation upon which future drug discovery and translational efforts can build to target human disease and ageing.
Cell Biology of Nutrient Sensing group
European Research Institute for the Biology of Ageing (ERIBA)
University Medical Center Groningen (UMCG)
Building 3226, Room 03.34
PO Box 196, Internal Zip Code FA50
9700 AD Groningen
The Netherlands
European Research Institute for the Biology of Ageing (ERIBA)
University Medical Center Groningen (UMCG)
Antonius Deusinglaan, 1
Building 3226
9713 AV Groningen
The Netherlands
