Objective
* To determine the mechanisms of action of alkyllysophospholipids (ALPs) against Leishmania and Trypanosoma cruzi , including effects on the host immune response
* To identify novel biochemical and molecular targets in Leishmania and Trypanosoma
* To establish ALP resistant clones and identify mechanisms of resistance
* To define interspecies and interstrain variation in sensitivity to ALPs
* To define a structure-activity relationship of the antileishmanial and antitrypanosomal activities of ALPs as they represent a new selective model for further antiprotozoal drug development
* To define rational drug combinations to be used in treatment.
Expected Outcome
* An understanding of the mechanisms of activity of a novel group of antiprotozoal drugs and the identification of novel drug targets
* Data on drug activities and drug combinations useful for clinical studies on leishmaniasis and trypanosomiasis
* PhD students will be trained in laboratories in Europe and South America and international links cemented.
* Results will be published in international journals, presented at international meetings and be the central focus of an EC meeting to which representatives of pharmaceutical companies will be invited.
* The activities of ALPs, alone and in combination with other drugs, will be determined against both exacellular and intracellular forms of different strains/species of Leishmania and Trypanosoma by microscopical and biochemical techniques.
* The effects of ALPs on membrane pathways, in particular sterol, lipid and glycosyl-phosphatidylinositol (GPI) anchor biosynthesis, will be studied.
* Effects on parasite differentiation and signal transduction will be examined in particular in relation to roles of protein kinases, phospholipases, calcium levels and adenylate cyclase.
* The uptake and distribution of ALPs by parasites and host cells will be measured by isotopic and chromatographic methods.
* Immunomodulating properties of ALPs will be studied in relation to killing of intracellular stages of Leishmania and Trypanosoma cruzi in macrophages.
* Resistant clones of Leishmania and Trypanosoma cruzi will be established through the stepwise exposure of extracellular parasites to increasing concentrations of ALPs.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences basic medicine pharmacology and pharmacy drug discovery
- natural sciences chemical sciences inorganic chemistry alkaline earth metals
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences basic medicine immunology
- natural sciences biological sciences biochemistry biomolecules lipids
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Coordinator
WC1E 7HT London
United Kingdom
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