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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Kinetics of Activation and Inactivation of Autophagy: Commitment, Noise Suppression and the Role of Metabolic Intermediates

Alternative title: Kinetikk for aktivering og inaktivering av autophagy: Forplikting, undertrykkelse av støy, og rollen av metabolske mellomprodukter

Awarded: NOK 12.0 mill.

During their lifetime, cells in most organisms experience some form of nutrient starvation. Cells activate certain mechanisms to survive such periods of low nutrient availability. One such mechanism is autophagy, which is a process that degrades non-essential cellular components to provide nutrients to keep the cell alive. Autophagy must be carefully controlled, because insufficient autophagy may not generate enough nutrients to keep the cell alive, whereas too much autophagy can result in degradation of essential components of the cell and cause cell death. However, how the cell controls the level of autophagy is still very poorly understood. In this project, we will unravel novel mechanisms by which the cell controls autophagy. What we are particularly interested in is how this process is regulated in populations of cells. Our preliminary studies have shown that activation of autophagy in populations of normal cells occurs rather simultaneously; most cells activate autophagy more or less at the same time and with the same amplitude. However, we have identified genes that, when inactivated, result in a much less synchronic response in cell populations. This suggests that the cells monitor to what extent this process has been activated. This project aims to understand these processes. During the past year we have been developing methods required for studying these processes, including advanced light microscopy and machine learning methods. We are now using these methods to study the effect a panel of selected genes on autophagy.

Nutrients like amino acids, lipids, and glucose and related sugars are simple organic compounds that are involved in biochemical reactions that produce energy or that constitute cellular biomass. Maintaining cellular homeostasis in the face of changes in nutrient supply is essential for the growth and development of all organisms, from unicellular microorganisms to higher eukaryotes. When a cell detects a loss of its nutrient supply, it activates signal transduction pathways that elicit integrated responses that alter cell metabolism (reducing biosynthesis and increasing catabolism) and that mobilize alternative nutrient sources. One key element of the response to nutrient starvation is activation of autophagy, which is a catabolic process that recycles cytoplasmic components through lysosomal degradation, thereby generating nutrients to sustain essential cellular processes. The upstream pathways that regulate the kinetics of autophagy in response to changes in nutrient conditions are only partially understood. In particular, the mechanisms that switch off autophagy when nutrient availability improves remain mysterious. Furthermore, our unpublished data suggest the existence of feedback loops that finetune autophagic output at the single-cell level and that suppress noise in the pathway, yet the underlying regulatory mechanisms remain largely unknown. These gaps in our knowledge need to be overcome if we are to understand how cells dynamically control autophagy, which is the goal of this project.

Funding scheme:

FRIMEDBIO-Fri prosj.st. med.,helse,biol

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