Despite its fundamental importance, our understanding of the immediate mechanisms directing tissue response and the complex cell-cell communications regulating its resolution remain fairly limited. Moreover, current anti-inflammatory drugs work relatively unspecific as on-off switches, thereby exhibiting considerable side effects. Studies on innate immunity have benefitted from the introduction of the transparent zebrafish larvae as an assay system. Transgenic fish expressing fluorescent proteins in leukocytes allow direct quantification of the inflammatory response in real-time in a live animal. However, the assays used to date require physical wounding of the fish preventing even a medium throughput experimental scale. We have developed a novel wounding assay without the need for mechanical wounding allowing high throughput large-scale analyses towards a comprehensive understanding of inflammation. Here, I propose the generation of an automated screening platform based on our specific non-invasive chemical wounding followed by automated microscopy and image acquisition that will allow the in vivo screening of thousands of compounds in a matter of days with respect to their effect on leukocyte recruitment, leukocyte function, resolution of the response and general toxicity in a single assay; target profiling of small molecule hits from by chemical proteomics and integration of acquired data into an interactive web-based repository aiming at an interconnected view of molecular networks guiding an innate immune response.
This platform will allow chemical and genetic screens to the identification of new molecular pathways involved in innate immunity. At the same time, our approach will identify lead compounds for the development of novel immuno-modulatory drugs with enhanced specificity allowing fine-tuning of inflammation by targeting particular aspects of an innate immune response.
Start Date: 2010-09-01 End Date: 2014-08-31 EU Contribution: 100 000 Euro Total Costs: 100 000 Euro Programme Acronym: FP7-People Subprogramme Area: FP7-PEOPLE-2009-RG Marie Curie Action: "Reintegration Grants"