Structure - Function Relationships in Protozoan Parasites Utilising High Resolution 3D Bioimaging

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The family Trypanosomatidae contains a number of important human-infective protozoan parasites. These include Trypanosoma cruzi which causes Chagas Disease in Central and South America and there are reported to be ~18 million people infected in some of the poorest communities with no long term effective drug treatment, particularly for chronically infected patients. Trypanosoma brucei is a closely related parasite that causes African sleeping sickness and kills ~50,000 people annually in Sub-Saharan Africa. The cattle species of Trypanosoma brucei has a devastating economic impact, with large areas of countryside that cannot be used due to the prevalence of the Tsetse fly, which spreads the disease. Both parasites are on the World Health Organisation list of 17 neglected Tropical Diseases and more efforts are required to understand the biology of these parasites to help find effective treatments.There are two aim objectives with 4 main research areas that will be developed within a context of modern molecular and cell biology of parasites and the use of novel three dimensional electron microscopy.These parasites have an indentation in the cell surface called the flagellar pocket, which is the major site of entry and exit of molecules, nutrients and entry of drugs and is a critical factor in the pathogenicity of these parasites. It has a complex three dimensional structure and we aim to use a range of three dimensional electron microscopy techniques to really understand how the flagellar pocket and associated structures divides and functions. These parasites have completed genome projects and a range of genetic tools to allow in-depth analysis of individual genes. The partners in both the UK and Brazil are experts in understanding the flagellar pocket structure of the two parasites. However, important differences are emerging through concerted efforts by both partners. These differences and similarities are important to understand, particularly as the flagellar pocket is a major site for entry of drugs and nutrients to these cells. Our objective is to run a fully collaborative project to understand these differences in further detail and the design of the visits between staff and students over the 3 years is aimed at maximising contact and discussion between the partners in the context of 4 experimental research areas. We will also organise a mini-symposium during year 2 to ensure that the outcomes of the experiments and conclusions can be disseminated to a wide academic audience, including those working with drug discovery, endocytosis (nutrient uptake in cells) and immunology.In order to really understand how living cells divide and interact with their surroundings we need to understand a detailed view of their three dimensional spatial organisation. This has been difficult to achieve using existing electron microscopes due to their inherent limitations. Recently, there have been significant developments in three dimensional electron microscopy to image the detailed structure of cells and tissues of organisms in an automated manner and the partners on this proposal are leading centres of excellence for these 3D microscopy techniques. The number of trained scientists is low both nationally and internationally and during the 3 year grant our aim is to train as many staff and students as possible as we believe these techniques will revolutionise general cell biology in the next 10 years.