INTERVENTION OF AUTOIMMUNE DISEASES BY A NOVEL ANTI-INFLAMMATORY MOLECULE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Autoimmune diseases like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD) are heterogeneous, chronic and relapsing inflammatory conditions that have a significant impact on the quality of life. Despite a wide variety of causes (e.g. environmental factors, genetic susceptibility, imbalanced enteric bacteria), the end-result is an abnormal immune response with repeatedepisodes of inflammation. Conventional treatment can reduce periods of active disease and help to maintain remission, but these treatments often bring marginal results, patients become refractory, and there are side effects. For this reason, there remains a need to find new therapeutic strategies to abate autoimmunity. The conversion of arginine to citrulline (an enzymatic reaction called deimination) is carried out by the peptidyl arginine deiminase (PAD) family of enzymes. This causes citrullination of proteins, which can alter their function. Recent evidence has identified citrullination as an inflammation-dependent process. Dr. Paul Thompson's lab at the University of South Carolina has novel and exciting data showing a novel PAD inhibitor (Cl-Amidine) decreases the incidence and inhibits inflammation in a mouse model of RA. We have exciting preliminary data indicating PAD levels are elevated in a mouse model of IBD, and in itchy mice (a mouse model of systemic autoimmunity). Interestingly, a genetic polymorphism in PAD4 has recently been reported to be associated with increased susceptibility to colitis, underscoring its emerging importance to this disease. We therefore aim to test the hypothesis that Cl-Amidine (a kind gift from Dr. Thompson) abates autoimmunity in these models. Overall, this project offers the unique opportunity to tie together the discovery of a novel compound with proven anti-inflammatory properties (Cl-Amidine) with the expertise of two investigators (Drs. Hofseth and Matesic) whom have working models of autoimmunity and chronic inflammation. Given the novelty and proven low toxicity of Cl-Amidine, results have the potential to: (1) be published as at least two papers in medium to high impact journals; and (2) lead to two investigator initiated RO1 grants.