TIMER objectives
Shifting inflammation from blockade to resolution
TargetIng novel MEchanisms of Resolution in inflammation
TIMER tests an active route out of inflammation: rather than only blocking mediators, the consortium looks for the molecules and pathways that let tissue resolve an inflammatory response.
The project involves discovery of new natural or synthetic proresolving molecules from plants and animals, and investigation of endogenous inflammation proresolving mechanisms, including atypical chemokine receptors, decoy receptors and microRNA. Efforts are mainly focused on the regulation by proresolving agents of two molecular systems of key relevance in inflammation: the chemokine system, which regulates recruitment, permanence and egress of leukocytes in tissues; and the Toll Like Receptor (TLR) / IL 1R system, which is central for the activation of infiltrating leukocytes.
Here we argue that pushing for inflammation resolution by exploiting active naturally occurring proresolving processes may have significant advantages over the attempt to simply push back inflammation by passive blockade of proinflammatory mediators.
Four strands of work
Receptors that shape chemokine availability and leukocyte traffic.
Endogenous mechanisms that dampen inflammatory signalling.
Post transcriptional control of proresolving programmes.
Plant and animal sources screened for new proresolving leads.
The consortium concentrates on agents that act on the chemokine system and on the TLR / IL 1R superfamily, because these two systems govern how leukocytes arrive, remain and leave a site of inflammation, and how they become activated once there.
The search covers both endogenous mechanisms identified by consortium partners and exogenous compounds of natural or synthetic origin. The project structure sets out how discovery moves through in vitro pharmacology and in vivo validation towards early clinical development.
Where the work leads
The consortium expects its activities to result in early clinical trials on a restricted number of compounds, in particular TLR7/8 partial agonists and evasins, and possibly new compounds emerging from the pipeline. Read the work package description.