Rheumatoid arthritis/Epigenetics

The Center for Experimental Rheumatology is part of the Zurich Center for Integrative Human Physiology (ZIHP), in turn member of the Life Science Zurich Graduate School (LSZGS), and serves as an institution for molecular research in the field of rheumatoid arthritis (RA) and related autoimmune diseases. The laboratory continues its pursuit of discovering, investigating and understanding key molecular and cellular events in RA, osteoarthritis, ankylosing spondilitis, progressive systemic sclerosis and pulmonary hypertension.

Epigenetic modifications in rheumatic and cardiovascular diseases including methylation, acetylation, sumoylation and microRNA, represent the major focus of our current research. The molecular and cellular basis of joint destruction in rheumatoid arthritis, osteoarthritis and ankylosing spondylitis, involves especially the search for novel genes and their signaling pathways ("Functional Genomics"). The laboratory explores the molecular and cellular mechanisms by studying the processes of synovial adhesion to cartilage and bone, the activation of synovial cells to invade and the cellular interactions with cells of the immune system. The role of microparticles and modulating gene expression are another focus of our interest. Suppressive subtractive hybridization and arrays are used to establish cDNA libraries of genes which are induced by various stimuli, including signaling via cytokine receptors and TOLL-like receptors. Somatic gene transfer is applied to inhibit synovial cell-mediated cartilage destruction in the SCID mouse model engrafted with normal human cartilage and rheumatoid synovial tissues or isolated cells. Anti-sense constructs, ribozymes, siRNA and antagomirs are used to identify specific targets for future therapeutical interventions. The model is further used to explore the effect of novel drugs from the pharmaceutical industry. Molecular mechanisms of fibrosis are investigated in progressive systemic sclerosis (scleroderma) and in pulmonary hypertension in another focus of our research. Specifically, hypoxia –induced pathways, expression of chemokines and growth factors are explored with regard to impaired angiogenesis and the excessive production of extracellular matrix. In close cooperation with the Department of Cardiology at the University Hospital of Zürich, we are studying the endothelial function in both rheumatic and cardiovascular patients. Novel investigations on fresh thrombi retrieved from myocardial infarcted patients explore the role of inflammation in the acute coronary syndrome. A new clinical Research Program has been developed entitled "Molecular Analysis of Gene Expression modulated by Novel Drug Therapies" to study the molecular effects of drugs on individual cells. By evaluating most comprehensively these changes, novel modes of action as well as unwanted side effects can be discovered to develop safer therapeutics.

Special Techniques and Equipment

Ex vivo gene transfer to synovial cells
Suppressive subtractive hybridization and gene arrays
Epigenetic analyses: acetylation, methylation, non-coding RNAs