This is a translational study which investigates the role of the autophagic process in the pathogenesis of Rheumatoid Arthritis (RA), starting from the molecular mechanisms involved in the early steps of autophagy, thus suggesting novel design approaches to discover and develop new drug compounds.
Autophagy is a highly dynamic and regulated process aimed at engulfing cellular components and damaged organelles in internal vesicles (autophagosomes) that then fuse with lysosomes. This process occurs at a basal level in most tissues and contributes to the steady-state turnover of cytoplasmic components. Autophagosomes may originate from different membrane sites, mainly Mitochondria associated membranes (MAMs), where raft-like microdomains are enriched.
Autophagy may represent a functional processing event creating a substrate for autoreactivity. Recently, we demonstrated that autophagy activate peptidyl arginine deiminase, generating citrullinated and carbamylated peptides in synoviocytes and fibroblasts.
This research program is focused on 5 main aims, which represent intermediate objectives:
1. Analysis of autophagy in patients with RA;
2. Analysis of the role of Mitochondria-associated membranes (MAMs) in the autophagosome formation and in the regulation of autophagy;
3. Analysis of the role of autophagy on post-translational modifications of proteins: a possible trigger for anti-citrullinated and anti-carbamylated peptide antibodies, the main serological markers of RA;
4. Analysis of the role of autophagy on extracellular vesicles in patients with RA: presence of citrullinated and carbamylated proteins;
5. Pharmacological regulation of autophagy. The effect of statins, cyclodextrins and hydroxicloroquine will be evaluated.
Research in this field may contribute to clarify whether pharmacological regulation of autophagy might modify the autoimmune response during RA, thus disclosing new potential therapeutic targets for autoimmune diseases.
