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Flagellum function in parasite and human model systems

Primary Supervisor: Dr Samuel Dean, WMS

Secondary supervisor: This depends upon the details of the PhD that I develop with the student. However it is likely to be one of Nick Waterfield (if developing antimicrobials), Karuna Sampath (if using zebrafish as a metazoan model system) or Anne Straube (if performing single molecule imaging or microtubule biochemistry).

PhD project title: Flagellum function in parasite and human model systems.

University of Registration: University of Warwick

Project outline:

African trypanosomes and their cousins (American trypanosomes and Leishmania) are flagellated parasites that cause diseases that are as diverse in their pathogenicity as they are in their spread around the globe. Together, these diseases kill tens of thousands of people each year, cause massive morbidity and economically devastating diseases of cattle. There are no vaccines and existing therapies are mostly toxic, impractical and ineffective.

Their most prominent morphological feature, the flagellum, enables their motility, sensory recognition of the host (human) and vector (insect) environment, and attachment of the parasite to vector surfaces critical for its life cycle. Flagellum motility is central for these parasites’ infection and spread. Understanding more about trypanosome flagellum function will help us understand their core cell biology and potentially inform new strategies to treat infections and prevent transmission.

Trypanosomes are a fantastic system in which to understand eukaryotic flagella. They exhibit the canonical structural features that are found in nearly all eukaryotic flagella/cilia, meaning that knowledge about trypanosome flagella is likely to be relevant to other systems, such as humans. Moreover, they have powerful and scalable reverse genetics tools and resources that make them amongst the most tractable of all eukaryotic model systems. Targeted gene tagging and mutagenesis, gene-specific RNAi and over-expression can all be performed at scale, with hundreds of mutant cell lines being generated and analysed in parallel. They have a high-quality, well annotated genome and the localisation of nearly all trypanosomes proteins is available from http://tryptag.org.

Defects in human flagella (also termed cilia) cause a class of human genet disease called “ciliopathies”. Ciliopathies are complex disorders caused by genetic mutations which result in defective or dysfunctional cilia in many organs of the human body. These mutations affect diverse systems, causing deafness, blindness, learning difficulties and other developmental disorders. Over 20 ciliopathies have been identified, affecting ~1 in 1000 people, and the genetic causes underlying them are often not clear. Moreover, it is likely that there are undiagnosed ciliopathies and there is an urgent need to understand more about human ciliary function.

My lab uses trypanosomes and cultured human cells as model systems to understand eukaryotic ciliary biology, with an over-arching aim to improve human health by addressing infectious and genetic diseases. Some projects focus on investigating uncharacterised trypanosome flagellum proteins to gain insights into trypanosome flagellum function because of their extraordinary tractability and their importance for parasite pathogenicity. Other projects investigate human motile cilia because of their direct relevance for human genetic diseases. Ultimately, we use the best system to address the question being investigated, and switch between systems to test different hypotheses. And we love innovating and inventing new technologies!

We are also interested in translational projects to find new ways to kill parasites and treat human and cattle diseases. This include using new biotechnological agents, identifying new antimicrobial peptides, or identifying new toxins specific to parasites.

If any of this sounds interesting, come and talk to me and I will show you around my lab.

TL;DR: My lab uses trypanosomatid parasites and human cells to study eukaryotic flagella. We do this because flagella are important - parasite flagella are essential for infection and spread and human flagella are associated with human genetic diseases. Projects are focussed on understanding flagella in one or both these systems by investigating uncharacterised genes.

Google scholar profile: https://scholar.google.co.uk/citations?user=g1pcd3sAAAAJ&hl=en

Lab webpage: https://warwick.ac.uk/fac/sci/med/research/biomedical/labs/sdean/

BBSRC Strategic Research Priority: Understanding the Rules of Life: Microbiology

Techniques that will be undertaken during the project:

    • Molecular biology and cloning (golden gate, Gibson assembly and traditional)
    • Genome sequencing and transcriptomics
    • Proteomics (immunoprecipitation, BioID, mass spectrometry)
    • Cell Culture and genome engineering (CRISPR gene-editing, gene mutagenesis and tagging)
    • Flow cytometry
    • Fluorescence microscopy (widefield and super-resolution, such as expansion microscopy)
    • Electron microscopy
    • Quantitative Western analysis
    • Protein purification for biochemical and structural assays
    • Single molecule imaging

    Contact: Dr Sam Dean, University of Warwick