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Periodic Report Summary - GENETICHTS REVEAL PF (Genetic High Throughput Screenings by random mutagenesis to identify Plasmodium falciparum critical genes for asexual growth, sexual differentiation ...

Summary of the Project Objectives Malaria is a global health problem that demands immediate practical actions to contain the high infection and mortality rates. Protective vaccine is still missing and resistance to anti-malarial drugs. is rising and expanding on the territories. While no vaccine of the current portfolio showed ideal protection level and low-cost feasibility, drug development is still limited to formulation renewals or chemical modifications of current drugs. Global health organizations committed to fight malaria indicate that among the primary goals there are rationalized vaccine projects and identification of novel targets to develop antimalarials that are new chemical entities. The foremost reason of the general stall on both vaccine development and drug discovery is the limited knowledge about general mechanisms regulating the complex Plasmodium life cycle and its interactions with the host. Despite In the past few decades Plasmodium research was significantly forwarded by the availability of new genetic tools, genome, microarray and proteomic data. Nonetheless, basic and important questions on Plasmodium biology are still shockingly unanswered. In particular, the field is still in great demand of approaches that allow discovering the biological function of about 1/2 of the genome encoding about 2,000 functionless proteins. In order to respond to these basic and priority questions p, we are developing novel genetic tools for random mutagenesis in Plasmodium falciparum that would permit mutant production on large scale. By using this tool we aim to investigate and characterize, genes and mechanisms that are involved in the host- -pathogen interaction, critical for asexual growth and sexual differentiation. Work performed since the beginning of the Project and general perspective The work done so far showed the feasibility of our main approach for inducible mutagenesis. We successfully tested the possibility to mutagenize P. falciparum by the use of a hyperactive transposase derived from engineered Sleeping Beauty. We are currently aiming for regulation of this transposase by the aid of small molecules using the destabilization domain and its genomic integration. This will greatly potentiate the yield of produced mutants since it will allow the expansion of parasite clones that contain the regulatable transposase before mutagenesis activation. In addition, positive fluorescent probes for integration are being developed and they will permit the sorting of mutants as they are produced. Concomitantly, high- and medium-throughput formats of screenings for phenotypic defects are being setup for genotypic and phenotypic analyses of the produced mutants. These assays mostly focus on asexual stages and gametocytogenesis and are designed to optimally counteract the availability of large numbers of random mutants. Our results will contribute significantly to the discovery of new targets to block asexual cycle and transmission forms, and for possibly to identify parasite virulence factors influencing host immune response. On the basis of the novelty and the high impact of this project, it is foreseen that the completion of our work will be a breakthrough in the field, opening investigation possibilities so far precluded. Our results will provide important advancements in Plasmodium genetic modifications. In addition, in order to provide the whole scientific community access to our mutants we will facilitate the creation of a reference library of mutants for future screenings. Our work has been designed to be a practical and solid contribution to the global Malaria fight exploring research areas of Plasmodium biology that, up to date, technical impedimenta rendered barely accessible.

Reported by

via del Giochetto
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