Periodic Reporting for period 4 - noRAG-TOR (Rag-independent regulation of mTOR by Amino Acids)
Période du rapport: 2022-08-01 au 2023-01-31
To explain the ERC-funded research that my group does to understand how cellular nutrient sensing works and how to tackle age-related diseases, I will adopt a simple example from nature: Some animals, like bears, hibernate. They are active, hunting in periods when sufficient food is available in their environment; in contrast, during the winter, when food is scarce, bears adapt by lowering their metabolism and ‘sleep’ until the conditions are optimal again. This is exactly what our cells also do! The trillions of cells in our bodies have very complex mechanisms to sense whether they have sufficient nutrients to support their functions and grow; or to lower their metabolic needs to cope with nutrient starvation. Why is this important? Back in our example, if a bear would stay active during the winter, it would not be able to cover its nutritional needs and would probably starve to death. Similarly, these sensing mechanisms are crucial for cells to properly adapt to their environment and can thus be detrimental for human health when they malfunction. Not unexpectedly, interventions such as dietary restriction or diet-mimicking drugs aim to restore these exact cellular mechanisms. So far, however, the use of such interventions in humans seems extremely challenging as they do not work for everyone and are too harsh to be tolerated by most people.
Our work aims to understand how precisely these molecular mechanisms work in healthy cells and what goes wrong in ageing and disease. By challenging and expanding the current consensus in the field, we aimed to identify novel, more targeted ways to modulate these crucial processes in the right organs, at the right time, and to the right extent. By increasing our knowledge on how nutrients—the food we eat—affect how our cells function, how we get sick, and how we age, in the future we will be able to suggest how to modify our nutritional habits or, more importantly, what exactly our pharmacological interventions should be targeting.
Our work aims to understand how precisely these molecular mechanisms work in healthy cells and what goes wrong in ageing and disease. By challenging and expanding the current consensus in the field, we aimed to identify novel, more targeted ways to modulate these crucial processes in the right organs, at the right time, and to the right extent. By increasing our knowledge on how nutrients—the food we eat—affect how our cells function, how we get sick, and how we age, in the future we will be able to suggest how to modify our nutritional habits or, more importantly, what exactly our pharmacological interventions should be targeting.
Unlike previous approaches, this project aimed to elucidate the Rag-independent modes of mTORC1 regulation by amino acids. To achieve this goal, we generated a number of Rag-mutant cellular systems, used pharmacological inhibitors, and established biochemical assays, proteomic approaches and functional RNAi screens. These tools allowed us to study the mechanistic aspects of mTORC1 activation, and to identify several novel mTORC1 regulators in Rag-mutant cells, thus building part of the Rag-independent mTOR regulatory network. Our findings are described in a number of peer-reviewed publications, pre-print articles, and unpublished manuscripts that are currently in preparation and will be submitted for publication after the end of the ERC funding period. Part of the data was also presented in seminar given in national and international venues, as well as in the 2019 WEF Annual Davos Meeting, and the Berlin Science Week 2019.
This project conceptually challenges and expands the current consensus in the field. Our data suggest the existence of new mechanisms and principles in mTORC1 activation and thus expand our view on how amino acids control its activity. In addition, our work provides novel mTORC1 regulators, as putative targets for drug development against mTOR-related diseases in the future.