PhD Cellular and molecular investigation of the role of the ubiquitously expressed thioesterase Ppt1

Vacancy Reference Number

2019-Eastbio-012

Closing Date

5 Dec 2018

Address

The Roslin Institute, University of Edinburgh

Ppt1 is a thioesterase. Thioesterases like all esterases, are enzymes that split off an ester into acid and alcohol in the presence of water specifically at a thiol group. Ppt1 catabolises lipids in lysosomes which are intracellular membrane bound organelles.

Very simplistically - Lysosomes function to break down waste biomolecules and are an essential part of the ‘waste disposal and recycling system’ of cells. They play a key role in cellular homeostasis with cell signalling and energy metabolism activities. Lysosomes are also the final step in the destruction of viruses and bacteria. Mutation of the genes encoding lysosomal enzymes are associated with a range of genetic diseases, collectively termed lysosomal storage diseases. 

As with many proteins currently known to be involved in regulating normal lysosome function, Ppt1 is ubiquitously expressed and does not appear to be required for normal prenatal development. Any yet perturbation in such a protein is capable of inducing a devastating postnatal neurodegenerative disorder in children, with Ppt1 being the most prominent disease causing lysosomal mutation in the American population and the second most prevalent worldwide. 

The relationship between the apparently ubiquitous 'housekeeping' activity of lysosome function and specific neural dysfunction is unclear. Whilst the neurodegenerative/neuronal focussed alterations are the most readily apparent presentation following altered expression of lysosomal proteins, it is not surprising that proteins such as Ppt1 have been implicated in other systems such as thermal regulation by brown adipose, in the testes and therefore possibly reproduction, and in monocytes suggesting a role in innate immunity.

Whilst the Ppt1 proteomic ‘interactome’ is beginning to be defined in established human neuronal-derived cell lines there is not much information on what Ppt1 interacts with in specific tissues and comparative studies in other mammalian systems have not been performed. 

We have access to existing murine models with the same Ppt1 mutation present as the human population and are also generating large animal models by editing the ovine & porcine Ppt1 gene. The ovine models are available now.

We therefore propose to use such animal models to investigate the tissue specific physiological role of Ppt1. By examining a broad range of cell and tissues types using tools such as proteomic techniques, this project will generate tissue specific Ppt1 ‘interactomes’. By doing this across multiple species and models we can also examine the influence of other factors including host species (mouse vs pig vs sheep vs human tissues where available) and expression levels (i.e. heterozygous vs homozygous comparisons). 

Verification of identified proteins and signalling pathways will involve analysis of tissues for the presence and distribution of the protein in association with other key markers. Selected tissue specific species independent perturbations will then be assessed for their potential role in governing stability of those tissues.

This project will expand our understanding of the role of the lysosome in animals, underpinning our knowledge of the normal healthy post-natal aging process.

Eligibility 

All candidates should have or expect to have a minimum of an appropriate upper 2nd class degree. To qualify for full funding students must be UK or EU citizens who have been resident in the UK for 3 years prior to commencement. 

How to Apply

Download application and reference forms via: https://www.ed.ac.uk/roslin/postgraduate/bbsrc-eastbio-dtp 

Applications:  Completed application form along with your curriculum vitae should be sent to our PGR student team at RDSVS.PGR.Admin@ed.ac.uk  

References:  Please send the reference request form to two referees. Completed forms for University of Edinburgh College of Medicine and Veterinary Medicine project should be returned to RDSVS.PGR.Admin@ed.ac.uk by the closing date: 5th December 2018.  It is your responsibility to ensure that references are provided by the specified deadline. 

For more information and to apply, click here

Contact Details

RDSVS.PGR.Admin@ed.ac.uk