Descrizione del progetto
Esplorare i meccanismi di autoimmunità dell’artrite reumatoride
Si stima che l’1 % della popolazione globale soffra di artrite reumatoide, una malattia infiammatoria autoimmune caratterizzata dalla presenza di autoanticorpi (quali gli anticorpi anti-proteine citrullinate) e da una grave infiammazione che danneggia le articolazioni periferiche, aggiungendo un onere significativo alla vita dei pazienti. Sfortunatamente, i meccanismi che causano l’insorgenza dell’infiammazione del tessuto nell’artrite reumatoide rimangono ignoti e ciò limita il successo del trattamento e della prevenzione. Per colmare questo divario, il progetto INSPIRE, finanziato dall’UE, condurrà una dissecazione spaziotemporale comprensiva e approfondita dell’infiammazione indotta dall’autoimmunità nell’artrite reumatoide. Si avvarrà di recenti innovazioni quali l’RNA a cellula singola e il sequenziamento mediante saggi di accessibilità della cromatina alle trasposasi (ATAC-seq) in combinazione con antigeni e dextrameri MHC con codifica a barre del DNA, trascrittomica spaziale e imaging rivoluzionario per spiegare i meccanismi dell’artrite reumatoide e consentire trattamenti innovativi.
Obiettivo
Rheumatoid Arthritis (RA) is a prototypic T cell- and B cell-driven inflammatory autoimmune disease that affects around 1% of the population worldwide and creates a severe burden for patients as well as substantial socioeconomic costs for society. Hallmarks of RA are a destructive inflammation of peripheral joints as well as the presence of autoantibodies such as anti-citrullinated protein antibodies (ACPA). Although ACPA are considered to represent major drivers of RA pathology, they can be also found in otherwise healthy “individuals at risk” where they emerge decades before the eventual onset of RA. Factors and mechanisms that promote onset of tissue inflammation in such autoantibody-positive individuals still remain elusive. Due to this gap of knowledge, current therapies are primarily designed to suppress later stages of joint inflammation, rather than targeting the underlying processes of autoimmunity or the initial onset of inflammatory disease. RA patients thus still lack effective preventive or curative therapeutic concepts. Here we aim to exploit recent technical breakthroughs such as single-cell RNA- and ATAC-sequencing in conjunction with DNA bar-coded MHC dextramers and antigens, spatial transcriptomics and cutting-edge imaging to perform a comprehensive and in-depth spatiotemporal analysis of the molecular events underlying the initial onset of inflammatory disease in autoantibody-positive individuals. We will additionally profit from the access to a large and well-characterized cohort of ACPA-positive “individuals at risk” and ACPA-positive RA patients as well as from corresponding biomaterial. In combination with preclinical animal models of RA, we thereby seek to delineate the sequences of events that promote the early transition from autoimmunity to inflammation. The obtained data will yield key insights into basic mechanisms of inflammatory autoimmune diseases such as RA and provide the basis for novel treatment concepts.
Campo scientifico
- medical and health sciencesclinical medicinerheumatology
- medical and health scienceshealth sciencesinflammatory diseases
- medical and health sciencesbasic medicineimmunologyautoimmune diseases
- medical and health sciencesbasic medicinepathology
- engineering and technologyindustrial biotechnologybiomaterials
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
10117 Berlin
Germania