Ricerc@Sapienza

This is a translational study in which, starting from the molecular mechanisms involved in the early steps of autophagy, we will investigate the role of the autophagic process in the pathogenesis of Rheumatoid Arthritis (RA), implementing a rational drug design approach to discover and develop new drug compounds.
Autophagy is a catabolic 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 peptides in fibroblasts and synoviocytes, with consequent triggering for anti-citrullinated peptide antibodies, the serological marker of RA. Thus, this research program is divided into 5 main objectives:
1.Analysis of the role of "raft-like microdomains" in the regulation of the signals involved in autophagy;
2.Analysis of a possible regulation of the autophagy at the level of MAMs;
3.Proteomic analysis of MAMs in the absence or following autophagic stimulus;
4.Analysis of the role of autophagy on post-translational modifications of proteins: a possible trigger for anti-citrullinated and anti-carbamylated peptide antibodies:
5.Synthesis and evaluation of the effect of heparanase inhibitors on autophagy modulation. All the compounds will be previously tested for selectivity, efficacy and safety.
Research in this field may contribute to clarify whether pharmacological regulation of autophagy might modify the autoimmune response and progression of RA, thus disclosing new potential therapeutic targets for autoimmune diseases.