Characterisation of SNA-2, a potential target for new drugs against parasitic nematodes.

Spliced leader trans-splicing is a conserved and essential step involved in gene expression in many animal and human parasites that is responsible for the formation of mRNA 5’ ends in these organisms. We are studying this process in nematodes, which include significant animal and plant parasites, such as Onchocerca volvulus, the causative agent of river blindness in humans. Our ultimate goal is the production of new drugs against these parasites. Our approach is to identify new drug targets among the proteins and RNA molecules involved in spliced leader trans-splicing in the nematode Caenorhabditis elegans. Because of the conservation of this process, knowledge gained C. elegans can be transferred to parasitic nematodes.

We have already identified SNA-2, an essential and conserved protein involved in spliced leader trans-splicing in nematodes (https://tinyurl.com/yxd633np, https://tinyurl.com/y4dcm769). This project will identify the precise function of this protein. You will use CRISPR/Cas 9 genome engineering to modify the C. elegans sna-2 gene so it expresses SNA-2 tagged with both a green fluorescent protein and an auxin-inducible degron. The green fluorescent protein tag will allow you to monitor the expression of SNA-2 during development and to determine the sub-cellular localisation of SNA-2 using fluorescence microscopy. It will further allow you to analyse protein and RNA interaction partners of SNA- 2. Proteins and RNAs that co-immunoprecipitate with SNA-2 will be identified by mass spectrometry and next generation sequencing, respectively. The auxin-inducible degron tag will cause rapid degradation of SNA-2 protein upon exposure of the animals to the small molecule auxin. This will allow you to determine the effect of the loss of SNA-2 function on animal development, and on gene expression, using RNA-seq for whole transcriptome analysis. Individual protein-protein and protein-RNA interactions will be further characterised using yeast-two-hybrid assays, and recombinant proteins for in vitro interaction studies.

Together, these state-of-the art experimental approaches will determine the precise role of SNA-2 in spliced leader trans-splicing and will identify critical interactions that may define target sites for new drugs. These will be further explored with collaborators specialising in drug discovery in the UK and overseas.

This project builds on our expertise in this area, and we have extensive experience with the experimental approaches you will take. We are located at the Institute of Medical Sciences of the University of Aberdeen, with access to excellent microscopy, proteomics and next generation sequencing facilities that support the project (https://tinyurl.com/yygdpluv).

APPLICATION PROCEDURE:
This project is advertised in relation to the research areas of MEDICAL SCIENCES. Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php. You should apply for Degree of Doctor of Philosophy in Medical Sciences, to ensure that your application is passed to the correct person for processing.

NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM.

Candidates should contact the lead supervisor to discuss the project in advance of submitting an application, as supervisors will be expected to provide a letter of support for suitable applicants. Candidates will be informed after the application deadline if they have been shortlisted for interview. Interviews are expected to take place on 23rd or 24th July 2019.