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Documents and Publications  >  report  >  PhD SCIENCE REPORT Lisa Riz...



Lisa Rizzetto

Predicted finish date for my PhD: February 2010

Our projects focuses on computational methods for the reconstruction of signalling pathways and the integration of gene expression data with existing biological information. In particular we target the response of dendritic cells to pathogenic and non pathogenic yeasts on a whole genome scale. At the same time our role in DC-THERA is to collaborate with bioinformaticians and with experimentalists for the solution of genomics problems that require highly interdisciplinary skills. We are also involved in the development of the DC-ATLAS initiative, where we have started the re-definition of intracellular pathway involved in DCs maturation process. Our project aims at establishing the computational methods to model the pathways of immune discrimination between pathogenic and non pathogenic microorganisms. We proposed to use different vegetative and non vegetative forms of the non pathogenic Saccharomyces cerevisae yeast to investigate the rules of the recognition game. Monocyte-derived dendritic cell (MoDC) recognized S. cerevisiae mainly trough fungal cell wall component recognition The different composition of cell wall in different growth conditions may influence the immune recognition of this yeast. In order to deeper insight the mechanisms of DC-S. cerevisiae interaction we evaluated the ability of vegetative and senescent cells of S. cerevisiae and Candida albicans to induce MoDC cytokine responses. By measuring cytokine production and priming of allogenic naïve CD4+ T cells, we observed that cells in different senescence states elicit peculiar immunological response. To reconstruct the signalling networks responsible for differences in the response we have performed transcriptional analysis of hMoDC and used Eu.Gene to reconstruct pathways and regulatory programs and compared with other experiments that we are collecting in a dedicated databases, DC-BASE. The development of DC-BASE is conducted in collaboration with Leaf Bioscience. The experience matured with Eu.Gene and pathways analysis will be relevant for the development of techniques to bridge ontologies and experimental data developed by Leaf Bioscience. In collaboration with Leaf Bioscience and the entire consortium we started the DC-ATLAS initiative. DC-ATLAS is a highly curated database of pathways of the dendritic cell, structured in a way to facilitate access to knowledge on biological mechanisms at the molecular level using representations that capture the hierarchical structure of signalling from receptors to effectors. The interactions in DC-ATLAS are cell-specific for DCs, manually curated and constructed using controlled vocabularies and hierarchies. In our lab we defined the pathway that we will curate, the controlled vocabularies that contain ontologically correct terms to define the pathway object, localization and type of reaction, cell type. We also started the curation of Dectin-1 signalling and TLR2 signalling, both involved in fungal recognition by DCs.

The predicted follow up of our activity is as follows: first, deeper insight into recognition of the different forms of S. cerevisiae to understand the mechanisms of fungi pathogenicity by in vitro and in vivo experiments. Second, we will complete DC-ATLAS with manual curated pathway dedicated to the DC cells.

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