Objetivo This proposal promises to transform our understanding of the basic biology of the malaria parasite Plasmodium, and of how that biology affects virulence. Remarkably little is known about the Plasmodium cell cycle, despite a wealth of knowledge on the subject in model cells. This project will reveal, with unprecedented resolution, how DNA replication is organised in Plasmodium and how changing conditions in the human host and exposure to antimalarial drugs affect it. Plasmodium is an early-diverging protozoan with a complex lifecycle & unusual cell-biological features. It replicates in its human host by ‘schizogony’: a single parasite generates many nuclei via independent, asynchronous rounds of genome replication prior to cytokinesis. This occurs over ~24hrs inside infected erythrocytes. However, the genome can also be copied extremely rapidly during the sexual cycle in the malaria-transmitting mosquito. Here 8 male gametes are produced from a single gametocyte in less than 10mins, necessitating extraordinarily rapid DNA synthesis. This project will first elucidate the spatio-temporal dynamics of DNA replication in these contrasting cell cycles. To do this, I have developed a method for labelling nascent DNA replication, which was not previously possible in Plasmodium. It will permit: a) a detailed characterisation, at the whole-cell level, of the asynchronous genome replication that occurs in schizogony; b) a study of replication origin spacing & DNA synthesis speed at single-molecule resolution on DNA fibres, comparing these parameters in schizogony & gametogenesis; c) mapping sequences with replication origin activity in the Plasmodium genome; d) investigation of cell-cycle checkpoints & replicative responses to the changing environment in the human host and to antimalarial drugs. These are crucial issues for understanding parasite virulence and drug-resistance, and the work will inform vital new research into transmission-blocking interventions for malaria. Ámbito científico medical and health scienceshealth sciencesinfectious diseasesmalarianatural sciencesbiological sciencesgeneticsDNAmedical and health scienceshealth sciencesparasitologymedical and health sciencesbasic medicinepharmacology and pharmacydrug resistancenatural sciencesbiological sciencesgeneticsgenomes Programa(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Tema(s) ERC-2016-COG - ERC Consolidator Grant Convocatoria de propuestas ERC-2016-COG Consulte otros proyectos de esta convocatoria Régimen de financiación ERC-COG - Consolidator Grant Institución de acogida THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE Aportación neta de la UEn € 1 801 331,64 Dirección TRINITY LANE THE OLD SCHOOLS CB2 1TN Cambridge Reino Unido Ver en el mapa Región East of England East Anglia Cambridgeshire CC Tipo de actividad Higher or Secondary Education Establishments Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Participación en los programas de I+D de la UE Opens in new window Red de colaboración de HORIZON Opens in new window Coste total € 1 801 331,64 Beneficiarios (2) Ordenar alfabéticamente Ordenar por aportación neta de la UE Ampliar todo Contraer todo THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE Reino Unido Aportación neta de la UEn € 1 801 331,64 Dirección TRINITY LANE THE OLD SCHOOLS CB2 1TN Cambridge Ver en el mapa Región East of England East Anglia Cambridgeshire CC Tipo de actividad Higher or Secondary Education Establishments Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Participación en los programas de I+D de la UE Opens in new window Red de colaboración de HORIZON Opens in new window Coste total € 1 801 331,64 UNIVERSITY OF KEELE ROYAL CHARTER La participación finalizó Reino Unido Aportación neta de la UEn € 197 364,36 Dirección KEELE UNIVERSITY FINANCE DPT ST5 5BG Keele Ver en el mapa Región West Midlands (England) Shropshire and Staffordshire Staffordshire CC Tipo de actividad Higher or Secondary Education Establishments Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Participación en los programas de I+D de la UE Opens in new window Red de colaboración de HORIZON Opens in new window Coste total € 197 364,36