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Elucidating the molecular mechanisms of diet-induced autophagy

Principal Supervisor: Dr Ioannis P. Nezis - School of Life Sciences

Co-supervisor: Dr Alex Cameron - School of Life Sciences

PhD project title: Elucidating the molecular mechanisms of diet-induced autophagy

University of Registration: Warwick

Project outline: 

UK has the highest level of obesity in Western Europe and its levels have more than trebled in the last 30 years. The cause of the rapid rise in obesity has been blamed on modern lifestyles, including high-calorie diet. The diseases associated with obesity are likely to be a huge burden for the healthcare system for many years to come. Therefore it is important to elucidate how diet and nutritional components function at the molecular and cellular level to regulate cellular processes.

Autophagy is an evolutionarily conserved process by which a portion of the cytosol and organelles are sequestered by isolation membranes. This forms a double-membrane-layered organelle called the autophagosome. The autophagosome can fuse with a lysosome and generate the autolysosome that has a single limiting membrane, where its contents are degraded. Autophagy is a cellular response in nutrient starvation but it is also responsible for the removal of aggregated proteins and damaged organelles and developmental remodelling. Recent research has indicated roles for autophagy in an increasing number of diseases, from bacterial and viral infections to cancer, and more recently in neurodegeneration and other ageing-related diseases and obesity. The process of autophagy is regulated by protein acetylation which is known to structurally interfere with protein-protein interactions. The molecular mechanisms that link the acetylation/deacetylation status of selective autophagy-associated proteins and their ability to bind to transcriptional factors that activate autophagy remains elusive. The aim of this project is to elucidate how diet-induced autophagy is activated at the transcriptional level. The main objectives of the project are:

  1. To examine whether diet regulate the aceylation/de-acetylation status of autophagy related proteins especially in the nucleus using cell biology, biochemistry and proteomics.
  2. To examine how acetylation mediates the interaction of autophagy related proteins with selective autophagy receptors and how this is repressing autophagy at the transcriptional level, using cell biology, biochemistry, structural biology and bioinformatics.
  3. To examine how autophagy related proteins are re-acetylated using cell biology and biochemistry.

References:

  1. 1. He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 43:67-93.

BBSRC Strategic Research Priority: Molecules, cells and systems

Techniques that will be undertaken during the project:

  • Basic cell, molecular biology and biochemistry
  • Drosophila genetics and cell biology
  • Confocal microscopy
  • Electron microscopy
  • Bioinformatics
  • Structural biology modelling

Contact: Dr Ioannis Nezis, University of Warwick