Genome editing and modelling to understand the biogenesis and function of a novel antiparasitic drug target

Supervisors: Jonathan Pettitt, Berndt Müller, Judith E. Sleeman, Ekkehard Ullner

Project Description:

We have identified novel factors involved in spliced leader trans-splicing, an essential step during nematode gene expression (  These factors represent ideal targets for the development of new drugs to treat parasitic nematode infections.

Animal and plant parasitic nematodes are a significant health and economic problem, and cause costs in excess of £1 Bn/year for crop protection, and in excess of £3 Bn/year for the protection and treatment of animals.  New drugs to fight these parasites are required as there is current and growing resistance to existing treatments.

The factors we identified are components of ribonucleoprotein complexes that participate in spliced leader trans-splicing, an essential RNA processing step that occurs in nematodes.  The precise functions of these factors are not understood. However, spliced leader trans-splicing is a nematode-specific process, and the factors are not found in the animal or plant hosts of parasitic nematodes, making them ideal targets for the development of antiparasitic drugs. 

The project will investigate the function of these factors in the nematode Caenorhabditis elegans by tagging them with fluorescent and affinity purification tags using CRISPR/Cas9 genome editing. This will allow us to characterise the dynamics of their subcellular distributions in wild type and mutant backgrounds. The approach will also allow the identification of the protein partners of these factors through immunoprecipitation/mass spectrometry. Interacting RNAs will be identified by crosslinking and immunoprecipitation (CLIP).

An important component of the experimental programme will be hypothesis testing through mathematical modelling of the dynamic cell biology. We propose that the novel ribonuclearprotein complexes act to recycle essential splicing factors, and we will explore this hypothesis through modelling, which will inform experimental pertubations to test predictions made by the models.

Together, this will identify critical interactions and functions of these factors, and thus inform rational drug design.

The project will provide training in widely applicable methods for genome editing and for the identification and characterisation of protein-protein and protein-RNA complexes, using the nematode C. elegans as a model system.  CRISPR/Cas9 technology is now the method of choice for editing genomes and is well established in the laboratory.  We have a strong track record in the analysis of protein-protein and protein-RNA complexes, and are supported by state-of-the-art proteomics and imaging core facilities at the University of Aberdeen. We have also specific expertise in the mathematical modelling of biological processes, and training will be provided in how to build and analyse mathematical models, and design experiments to test and parameterise these models.

The project is suited for a student with a strong background in molecular biosciences and an interest in quantitative biology.

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Blumenthal, T. 2012. “Trans-Splicing and Operons in C. elegans.” Edited by The elegans Research. WormBook. doi:10.1895/wormbook.1.5.2.

Philippe, Lucas, George C. Pandarakalam, Rotimi Fasimoye, Neale Harrison, Bernadette Connolly, Jonathan Pettitt, and Berndt Müller. 2017. “An in vivo Genetic Screen for Genes Involved in Spliced Leader Trans-Splicing Indicates a Crucial Role for Continuous de novo Spliced Leader RNP Assembly.” Nucleic Acids Research 45 (14): 8474–83. doi:10.1093/nar/gkx500.