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Reprogramming autophagy to fight neurodegeneration

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

Co-supervisor: Dr Antonia Sagona - School of Life Sciences

PhD project title: Reprogramming autophagy to fight neurodegeneration

University of Registration: Warwick

Project outline: 

Autophagy is an evolutionarily conserved process where the cells degrade their own cellular material. During autophagy, there is sequestration of cellular material into double‑membrane vesicles called autophagosomes. The autophagosomes fuse with lysosomes where the sequestered cargoes are degraded by lysosomal hydrolases. The products of degradation are transported back into the cytoplasm through lysosomal membrane permeases and can be reused by the cell. Autophagy is implicated in tumor suppression and progression, neurodegeneration, myopathies, lung and heart disease, diabetes, infections, and obesity. It is therefore very important to elucidate the mechanisms of autophagy in normal and pathological conditions (1).

Although it was initially believed that autophagy occurs randomly inside the cell, during the last years there is growing evidence that sequestration and degradation of cytoplasmic material by autophagy can be selective through receptor and adaptor proteins. To address the role of selective autophagy during ageing and neurodegeneration, the fruit fly Drosophila melanogaster will be used as a genetically modifiable model organism (2). The major aim of this project is to construct novel in vivo synthetically controlled autophagic machinery using a combination of synthetic biology, cell biology, genetics and bioinformatics. The main objectives of the project are: 1) To reengineer an autophagic machinery in Drosophila programmed against selected targets in vivo. 2) To test whether the reengineered autophagic machinery can ameliorate disease-phenotypes in Drosophila models of human neurodegenerative diseases

References:

  1. Yang Z, Klionsky DJ. (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol. 12:814-22.
  2. Neufeld TP, Baehrecke EH. (2008)Eating on the fly: function and regulation of autophagy during cell growth, survival and death in Drosophila. Autophagy 4:557-62.

BBSRC Strategic Research Priority: Molecules, cells and systems

Techniques that will be undertaken during the project:

  • Molecular biology
  • Drosophila genetics and cell biology
  • Synthetic biology
  • Confocal microscopy

Contact: Dr Ioannis Nezis, University of Warwick