Disease modification in rheumatoid arthritis using AMPK directed therapies: Restoring metabolic balance to innate immune pathways

Rheumatoid Arthritis (RA) is a chronic inflammatory disease affecting 1-2% of the population. Over time, RA causes joint destruction, chronic pain and lifelong disability. In addition to these effects, increased resistance to the effects of insulin and alterations in glucose handling mimicking effects seen in type II diabetes occur in RA. Adverse effects including premature frailty from muscle wasting and damage to blood vessels leading to heart attack and stroke, contribute to increased morbidity and mortality in both diseases.
AMP-activated Protein Kinase (AMPK) is a cellular enzyme, which is exquisitely sensitive to low energy levels during times of starvation. When activated by low cellular glucose levels, AMPK dramatically slows cellular metabolism through a combination of reduced glucose consumption, and by disabling cell processes like cell replication, protein synthesis and inflammatory responses that consume excess energy. There is growing evidence that AMPK becomes switched off not only by the high glucose levels seen in diabetes, but also in cancer cells leading to the growth and spread of cancer, and within inflammatory cells where runaway increases in glucose consumption in a process known as aerobic glycolysis provides fuel to the fire of unbridled inflammation.
Despite the fact that there is a wide body of evidence that existing and experimental medical therapies can switch off inflammation by activating AMPK, this has still not been tested in inflammatory diseases like RA. In this pre-clinical study using an array of approaches on living tissues including tissue taken from the inflamed joints of RA patients, we will directly test AMPK activating compounds to prove that they can be used in medicine to stop inflammation in RA. We believe that results from this study will lead directly to new AMPK directed therapies with better long-term disease outcomes for patients with RA and other inflammatory diseases.

Award Date
20 June 2014
Award Value
€329,799
Principal Investigator
Dr Ronan Mullan
Host Institution
Trinity College Dublin
Scheme
Health Research Awards