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Content archived on 2024-05-27

Cyclic amp-mediated cell cycle control in african trypanosomes

Objective

Trypanosoma is a protozoan pathogen endemic to Africa that causes human sleeping sickness and that is among the most important causes of livestock morbidity and mortality in Africa and parts of South America. Due to the current resurgence of the disease an increasing number of EC citizens will be at risk through tourism and business in Africa as well as during humanitarian interventions. The current widespread use of highly toxic drugs for chemoprophylaxis in livestock in Africa and South America may also threaten European consumers. The animal disease is a major factor in rural development in many African countries and has strong impact on their economies and thus their potential as trade partners for the EU. Drugs for safe, effective and inexpensive treatment are not available. Infective forms of Trypanosoma brucei undergo irreversible growth arrest and differentiation at high parasite density in the mammalian bloodstream. A specific arrest in the G0 phase of the cell cycle is mediated by a parasite derived factor that acts via the cAMP signalling pathway. Three apparently non-redundant protein kinase A (PKA) isoforms were identified. Here, a reverse genetic analysis of PKA function is proposed to validate the signalling pathway as a drug target. The regulated phosphorylation and mode of activation of T. brucei PKA that appears to deviate from mammalian PKA will be analysed. Cloning of cell cycle regulators known to be cAMP-modulated in other systems will be attempted.

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