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How changes in nutrient availability are sensed and shape metabolism and growth

Reference	BBS/E/B/000C0432
Principal Investigator / Supervisor	Dr Simon Cook
Co-Investigators / Co-Supervisors	Dr Michael Coleman, Dr Oliver Florey, Dr Phillip Hawkins, Dr Nicholas Ktistakis, Professor Len Stephens, Professor Michael Wakelam, Dr Heidi Welch
Institution	Babraham Institute
Department	Babraham Institute Department
Funding type	Research
Value (£)	7,076,740
Status	Current
Type	Institute Project
Start date	01/04/2017
End date	31/03/2023
Duration	59 months

Abstract

In mammals nutrient signalling is a multi-layered network that embraces physiological, cellular (eg autophagy, see objective 4) and organ systems (eg neural). The network maintains the internal environment in the face of changes in the availability of nutrients, simultaneously adjusts metabolism to mitigate against those changes and tailors cell growth throughout the body to fit the nutritional circumstances. We remain ignorant of many molecular details and systems-levels principles by which this system works. There is increasing interest in the possibility of slowing or reversing the effects ageing by dietary manipulation and/or use of pharmaceuticals such as rapamycin (an mTOR inhibitor), PI3K inhibitors or metformin (an indirect activator of AMPK) that act to suppress nutrient signalling. To proceed down this road rationally it is important we understand the molecular basis of any strategy to minimise unwanted side effects. At the centre of nutrient signalling is mTOR, a protein kinase and integrator of signals relaying information about a cells current environmental conditions, including nutrients (most conserved and powerful are amino acids but also; cellular energy status as read-out by AMPK and nutrientsensitive growth factors such as insulin, IGF-1 and EGF), stresses and the cell cycle29. If cellular conditions are satisfactory mTOR is active and coordinates, via direct phosphorylation of targets and indirectly via many changes in gene transcription, increased lipid, nucleotide, protein and carbohydrate synthesis and ATP and NADH production (collectively termed anabolic metabolism) to support growth. If conditions are unfavourable mTOR is inactivated and engages a huge range of processes to adapt, including increased autophagy and reduced anabolic metabolic activity (collectively termed catabolic metabolism). Work with many model organisms supports the concept that the anabolic mode reduces, and the catabolic mode extends, life span.

Summary

unavailable

Committee	Not funded via Committee
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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