TIMER project structure
The major thrust of the project will be on the development of strategies promoting resolution of inflammation by targeting prime movers of the inflammatory reaction: inflammatory chemokines and their receptors, which are key elements in dictating leukocyte infiltration, and the members of the TLR/IL-1R superfamily, which are major leukocyte activators. Pipeline activities are depicted in the Figure on the right.
The project capitalizes on the strong background of productive collaborative interactions among members of the consortium involving European and Brazilian participants. An additional strategic strength of the consortium is represented by the proven capacity to identify new molecules of synthetic or natural origin with a potential for application in humans. In particular, 6 out of 10 members of the Consortium have been part of the European Commission-funded project INNOCHEM, which also included one participant from Brazil (Beneficiary 2).
The project consists of two lines of activities: discoveries on endogenous and exogenous inflammation "pro-resolving" agents (which represent WP1: discovery). This will lead to in vitro studies in cell-based model systems for the definition of target specificity and mechanism of action, and structure activity analysis (WP2: In vitro pharmacology). The Consortium will mainly focus its activities on two key complex molecular systems, responsible for leukocyte recruitment (chemokines) and their activation (the TLR/IL-1R system) respectively. This will take advantage of the well documented expertise in in vitro analysis of these molecular systems of several European beneficiaries, which also have generated a number of original tools (polyclonal and monoclonal antibodies, cell transfectans, cell-based assays, gene-targeted animals) now available to the Consortium.
Molecules with promising biological profiles in vitro will then undergo pharmacological characterization and assessment of therapeutic potentials in inflammation and resolution experimental models (WP3: In vivo validation). A wide range of preclinical models of immunopathology, covering a variety of tissues (joint, skin, lung, colon) and mechanisms of diseases, are available to the Consortium, largely based on efforts conducted by the Brazilian beneficiaries. These preclinical models will provide validation of the molecules and targets identified in the pipeline.
Finally, to explore the impact on regulation of pathways of resolution in man by compounds investigated, it is expected that, TIMER activities will eventually result in conducting early clinical trials on a restricted number of compounds (WP4: Early clinical development). In particular, the Consortium will be involved in early exploratory (phase I/II) studies on TLR7/8 partial agonists and evasins, and possibly new compounds emerging from the pipeline.
In addition to these four R&D WPs, the dissemination of results and the successful progress of the TIMER project being ensured by two complementary WPs dedicated to dissemination and training (WP5), and to management (WP6).