A genome wide systematic deletion analysis of Plasmodium berghei protein kinases to reveal molecular mechanisms of life cycle regulation. (360G-Wellcome-078335_Z_05_Z)

The genome-wide functional analysis of protein kinases in model organisms is beginning to provide exciting new insights into the molecular regulation of basic cellular processes1-3. In malaria parasites we are beginning to appreciate the functions of protein kinases as key regulators of the life cycle. Gene knock-out parasites in Plasmodium berghei have recently shown essential, stage-specific functions for unusual protein kinases in cell cycle progression, motility and host vector interactions4,5[and our unpublished data]. We now propose to combine the in silico analysis of the complete complement of protein kinases in P. falciparum6 with recent advances in gene knock-out technology in P. berghei to carry out a systematic deletion analysis of the approximately 70 protein kinase-like genes we identified in P. berghei. Deletion mutants generated in the asexual erythrocytic phase of the parasites' life cycle will be transmitted to Anopheles stephensi mosquitoes and their phenotypes analysed to map kinase functions throughout the life cycle. We expect to gain important new insights into molecular mechanisms of parasite transmission and life cycle progression by identifying pathways regulating poorly understood processes, such as the switch to sexual development, cell cycle events during sexual differentiation and sporogony, which may serve a model for schizogony. The project will also generate a list of protein kinases with likely essential functions in schizogony. Recognising that protein kinases are now major targets for the development of selective inhibitors7, these will be important candidates for evaluation as drug targets.