Report
Teaser, summary, work performed and final results
Periodic Reporting for period 2 - MCTRinIA (Resolution Pharmacology and Physiology of MCTR in Arthritis)
Teaser
Chronic inflammation may result from failure of the host response to engage pro-resolving pathways. The current treatment armamentarium for chronic inflammatory conditions may lead to immune suppression. Thus, identification of novel therapeutics that control inflammation...
Summary
Chronic inflammation may result from failure of the host response to engage pro-resolving pathways. The current treatment armamentarium for chronic inflammatory conditions may lead to immune suppression. Thus, identification of novel therapeutics that control inflammation without immune suppression will provide an attractive alternative approach. This is especially important since incidence of these conditions increases with an ageing global population. In planaria, mice, human peripheral blood and milk I recently uncovered a new family of endogenous molecules, named Maresin Conjugates in Tissue Regeneration (MCTR). These potently regulate white blood cell responses, promote the resolution of acute inflammation and accelerate tissue regeneration. The aim of this Starting Grant is to identify pathways that lead to failed resolution in inflammatory arthritis, as a prototypical chronic inflammatory condition. The hypothesis is that MCTR biosynthesis is dysregulated in inflammatory arthritis, leading to an unbridled host response, chronic inflammation and tissue destruction. This proposal will employ a multipronged approach to test this hypothesis by 1) Determining MCTR regulation in self-resolving and delayed-resolving arthritis; 2) Investigating the host protective and tissue regenerative actions of MCTRs in inflammatory arthritis; 3) Establishing the MCTR biosynthetic pathway and 4) Determining the regulation if its components during self-limited and delayed-resolving arthritis. Anticipated results will uncover novel pathways that become dysregulated during failed resolution. Results from this Starting Grant will also identify targets and new therapeutic approaches that will engage pro-resolution programs as well as tissue regeneration in conditions characterised by persistent inflammation and hence failed resolution. This will lay the basis for informed structure-activity based studies and the design of therapeutics for treatment of chronic inflammatory conditions.
Work performed
Results from experiments performed so far in MCTRinIA have identified the enzymes involved in the production of the three molecules that compose the MCTR family of mediators. These findings have also demonstrated the interrelationship of the three molecules as well as the dynamics in their regulation during joint disease. These results have also established the correlation between the production of these molecules and the regulation of cellular recruitment into the joint, joint damage and joint inflammation. We have also established the ability of MCTRs to regulate joint inflammation as well as the underlying mechanisms via which they exert these protective actions.
Final results
Results from the present findings identify a novel approach for the regulation of chronic inflammation utilizing MCTRs to actively reprogram the inflammatory instead instead of inhibiting inflammation, which is the paradigm currently used in treating patients with rheumatoid arthritis, thus potentially providing a potential step change in the treatment of these patients.