Inserm researcher at Institut Necker-Enfants Malades (INEM), Ganna Panasyuk wishes to deepen her understanding of how cells identify and use the nutrients they need, and how they know where and when to use them. More specifically, her research project intends to elucidate a poorly understood aspect of cellular metabolism: the role of the degradation pathways and how their dysfunction impacts health. She has recently obtained a European Research Council (ERC) Consolidator Grant in order to help her do just that.
What is the aim of your ERC-funded project?
The general objective of my project - Metabolic integration by nutrient SENSing (MetaboSENS) - is to elucidate the mechanisms governing cellular metabolism, namely the various reactions that enable cells to synthesize (anabolism) or break down (catabolism) molecules to fulfill their functions, grow and multiply. It is an important subject because metabolic changes are linked to, or even responsible for, many diseases.
The mTOR protein has proved essential in controlling growth-related processes: activated by the presence of nutrients (amino acids, glucose), it goes on to trigger cascades of metabolic reactions that stimulate cell growth. These dysfunctions are linked to a number of diseases, such as cancer and diabetes. This protein is particularly interesting given its presence in all eukaryotic cells - from yeasts to mammals - reflecting its key role in metabolism.
My aim is to create a basic-research domain on signaling pathways that can counteract the one controlled by mTOR. We are convinced that there is another pathway that controls the degradation processes. We base this on the fact that, in yeast, the autophagy mechanisms that are established in the event of nutrient restriction depend on a protein complex (VPS34 and VPS15) which, like mTOR, has been held on to over the course of evolution. In humans, this protein complex goes by the name of class III PI3Kinase. We suggest looking at which metabolic activities it controls and through which mechanisms it acts. We also want to know whether its dysfunction is linked to human pathologies.
What makes MetaboSENS a novel project?
The fact that it is highly integrative. Starting from questions on cell function, we try to qualify the impact of class III PI3-kinase on the overall mouse metabolism and then identify whether the dysfunctions of this complex occur in rare human metabolic diseases.
We have obtained encouraging initial findings in a mouse model created by our team, in which the absence of this enzyme in the liver leads to very serious metabolic dysfunction.
Finally, we have a conducive research environment at our disposal on the Hôpital Necker campus at Institut Necker-Enfants Malades. Thanks to the doctors associated with the team, we will explore rare diseases whose causes have not been identified, in order to search for potential deficiencies in class III PI3-kinase functioning. We will also be able to use the campus’ federative research structure platforms for our analyses (genetic, metabolic, transcriptional, etc.).
How will you use the ERC funding?
This grant of 2 million euros over 5 years will enable us to fund the molecular analyses and create other mouse models in order to discover the role of this signaling pathway in metabolism. It will give us excellent international visibility and enable us to grow our team by hiring the best scientists to succeed in this challenge. It is a fantastic boost for this new field.
Is it the culmination of a journey?
I find metabolism to be a fascinating field because it forms the basis for life. For my Ph.D., I researched the principal growth regulation pathways (mTOR, PI3K, S6K) in Valeriy Filonenko’s laboratory in Kiev (Institute of Molecular Biology and Genetics), in close collaboration with the Ludwig Institute for Cancer Research in London. My future professional orientations became clear during a postdoc in Ivan Gout’s laboratory at University College London, where I discovered a short form of the mTOR protein, implicated in cancer proliferation. That was when I knew I wanted to continue to focus on metabolism regulation pathways - but in combination with work on animal models and human pathologies. I joined Mario Pende’s Inserm team, first as a postdoc and then as a researcher, specializing in PI3-kinase signaling pathways. In 2016, I received a French National Research Agency (ANR) young researcher’s grant enabling me to perform the research that supported my ERC grant application.