Investigating mechanisms of microparticle production by microvascular endothelial cells and defining clinically useful inhibitors
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To study the role of microparticles in causing a major complication of malaria infection, namely cerebral malaria.
Fatal malaria is one of the most destructive and potentially correctable disease burdens in the world, affecting mainly children. A major complication is cerebral malaria (CM). Current therapies are limited by our lack of knowledge of the pathophysiological events. We recently demonstrated that microparticles (MP), which we found to be present in greatly increased concentrations in the peripheral blood of Malawian children with CM, are crucial elements of pathogenesis in experimental CM. Based on these findings, we now aim, in vitro and in vivo, to demonstrate that by modulating the process of vesiculation (i.e. by reducing the production or release of MPs, or by blocking their toxic effects) we can reduce the pathological processes characteristic of CM. The ultimate aim is to reach a novel intervention for preventing the progression of severe malaria towards a fatal outcome and for hastening recovery from severe malarial disease. In our current projects, we therefore intend to unravel the mechanisms of MP production and action, to delineate pharmacological ways to interfere with these mechanisms, and to define the pathophysiological consequences of excessive MP production. Practically, we will perform co-cultures of human brain microvascular endothelial cells with parasites and blood cells. Purified MP will be added, to assess the functional consequences, notably on monolayer permeability and trans-endothelial electrical resistance. Various inhibitors of intracellular pathways will be added, to assess their ability to reduce the number of MP released upon stimulation by parasites, or to alter their phenotype. We also will define further the immunological and haemostatic parameters of the MP produced in these co-cultures settings.
Approaches: Immunology, Haematology, Pathology, Physiology, Cell Biology, Molecular Biology Techniques: cell culture, flow cytometry, cytofluorimetry, trans-endothelial electrical resistance, magnetic cell sorting, fluorescence microscopy.
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malaria, vascular diseases, inflammation, Endothelium, cytokines, immunopathology, Brain & nervous system disorders, Cardiovascular & respiratory diseases, Infectious diseases, Cell biology, Human body, Infection & immunity, Heart & circulation
The opportunity ID for this research opportunity is: 119