Objective Degradation of sphingomyelin (SM) by a sphingomyelinase (SMase) generates ceramide, a lipid metabolite increasingly recognised as an important pro-apoptotic mediator. The exact role of ceramide in apoptosis is unclear and aspects such as the source SM pool, and whether a membrane-associated neutral SMase (nSMase) or a lysosomal acid SMase is primarily involved, remain also to be defined. In this project, we will exploit the Listeria model of intracellular parasitism and an nSMase produced by these pathogenic bacteria, SmcL, identified and characterised in the host laboratory, to gain a better understanding of the role played by ceramide in host cell physiology, with particular emphasis on the apoptotic response. SmcL also provides a beautiful model to analyse how mimicry of host cell physiological functions by bacterial virulence factors contributes to the pathogenesis of infection.The host cell responses associated to SmcL-generated ceramide will be analysed during intracellular infection by using genome-wide transcriptome profiling and the specific pathways affected will be dissected by using a combination of molecular and cell biology techniques. Finally, we will also attempt to crystallise SmcL in collaboration with structural biologists. If successful, S mcL will become the first example of the neutral SMase family, a new group of SM-degrading enzymes comprising bacterial and eukaryotic orthologues with roles in virulence and signalling, to be characterised structurally. Fields of science natural sciencesbiological sciencesmicrobiologybacteriologynatural sciencesbiological sciencescell biologynatural sciencesbiological sciencesbiochemistrybiomoleculeslipidsnatural sciencesbiological sciencesbiological behavioural sciencesethologybiological interactionsnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Keywords Intracellular parasitism Listeria apoptosis cell-signalling ceramide host-pathogen interactions pathogenesis sphingomyelin sphingomyelinase structural mimicry Programme(s) FP6-MOBILITY - Human resources and Mobility in the specific programme for research, technological development and demonstration "Structuring the European Research Area" under the Sixth Framework Programme 2002-2006 Topic(s) MOBILITY-2.1 - Marie Curie Intra-European Fellowships (EIF) Call for proposal FP6-2002-MOBILITY-5 See other projects for this call Funding Scheme EIF - Marie Curie actions-Intra-European Fellowships Coordinator UNIVERSITY OF BRISTOL EU contribution No data Address Senate House, Tyndall Avenue BRISTOL United Kingdom See on map Links Website Opens in new window Total cost No data
