From molecular discovery to early clinical work

The major thrust of the project is the development of strategies that promote the resolution of inflammation by targeting 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.

The project builds on a strong background of productive collaborative interactions among members of the consortium, involving European and Brazilian participants. An additional strategic strength is the proven capacity to identify new molecules of synthetic or natural origin with a potential for application in humans. Six of the ten members of the consortium took part in an earlier European Commission funded project, which also included one participant from Brazil.

The project consists of two lines of activity: discoveries on endogenous and exogenous inflammation proresolving agents, which represent WP1, discovery. This leads 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 focuses mainly on two key complex molecular systems responsible for leukocyte recruitment, the chemokines, and their activation, the TLR / IL 1R system. This takes advantage of the well documented expertise of several European beneficiaries in the in vitro analysis of these systems, and of original tools they have generated, including polyclonal and monoclonal antibodies, cell transfectants, cell based assays and gene targeted animals.

Molecules with promising biological profiles in vitro then undergo pharmacological characterisation and assessment of therapeutic potential in inflammation and resolution experimental models, WP3, in vivo validation. A wide range of preclinical models of immunopathology is available to the consortium, covering a variety of tissues such as joint, skin, lung and colon, and mechanisms of disease, largely based on work conducted by the Brazilian beneficiaries. These models provide validation of the molecules and targets identified in the pipeline.

To explore the impact on the regulation of resolution pathways in humans, TIMER activities are expected to result in early clinical trials on a restricted number of compounds, WP4, early clinical development. In particular, the consortium is involved in early exploratory studies, phase I and phase II, on TLR7/8 partial agonists and evasins, and possibly new compounds emerging from the pipeline.

In addition to these four research work packages, dissemination of results and the successful progress of the project are ensured by two complementary work packages dedicated to dissemination and training, WP5, and to management, WP6.