Title: Mitochondrial dysfunction as a therapeutic target upstream of interferon type 1 in rheumatic disease
Funder: Versus Arthritis

Abstract: Why do we want to do this project? Juvenile dermatomyositis (JDM) is a rare autoimmune condition in which the body’s defence system (designed to stop infections) attacks muscles and skin leading to muscle weakness and skin rashes. Treatments used in JDM suppress the body’s defence system. These medications do not work for all patients and can cause unwanted side effects. The lack of effective drugs makes the already severe impact of the condition on a child/young person's life worse. If we could understand exactly which part of the body’s defence system was going wrong it would help us target this with more effective medication. We have examined genes (the human code) and the pattern of expression of these genes in immune cells from JDM patients. We discovered that genes that code for mitochondria (the ‘powerhouse’ energy producers of the cell) were less active in JDM patients (even those already on strong treatment compared to healthy children of the same age). We also found that markers of inflammation were more switched on in these same JDM patients. We believe that these discoveries now allow us to look for new and very specific drugs to improve the treatment of JDM and other autoimmune conditions such as juvenile systemic lupus erythematous (JSLE) and adult dermatomyositis (DM). What we would like to do? To identify if the changes in these gene expression patterns are important more widely than JDM, we will investigate if the same genes show changes in other childhood autoimmune conditions like; JSLE and juvenile idiopathic arthritis (JIA) compared to healthy young people of the same age. We will also examine if these changes are found in DM compared to healthy adults, to see whether the age at which someone first gets the condition makes a difference in how it develops. This project will investigate problems with the function of mitochondria and how these could link to inflammation, in both young people and adults with autoimmune conditions. We are very lucky to be able to include samples from large numbers of patients with JDM, JSLE, JIA, DM and healthy controls. We will : Identify changes in mitochondrial gene patterns in patients with JDM, DM, JSLE compared to JIA and controls Investigate problems with mitochondrial function using blood samples from patients with JDM, DM, JSLE compared to JIA and controls Use healthy human immune cells to test whether problems with mitochondrial function can cause inflammation and if this can be blocked by anti-oxidant drugs, which prevent damage to the cell What will the results show? This study is important because almost nothing is understood about what causes JDM and similar diseases such as JSLE and DM. This is stopping new treatments being created or used in patients. Problems with mitochondrial function have not been investigated in young people with autoimmune conditions before. If we receive funding we will be the first to do this work. This project could help us find and test new, better drugs which are key to improving patients’ lives.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD;INFLAMMATORY AND IMMUNE SYSTEM