Kromatinbindande egenskaper av survivin och dess betydelse för T-cellutveckling och behandlingeffekt vid reumatoid artrit

Maria Bokarewa, Göteborgs universitet, 100 000 kronor

Bakgrund och motivering

Survivin emerged as an essential part of RA pathology by pinpointing RA patients in the risk group, predicting severe RA course at diagnosis and by distinguishing drug-specific treatment responses. Thus, survivin provides a key to understanding the network of molecular events triggering and maintaining autoimmune arthritis. Recently, we described the critical role of survivin bound to chromatin in metabolic adaptation of CD4+T cells, and in histone H3 modifications by counteracting methyltransferase EZH2.

Syfte och mål

Specific goals:

To demonstrate a necessity of the survivin-dependent chromatin remodelling for development of the aberrant immunological memory in T cells;

To explore the relevance of environmental factors on the survivin-dependent chromatin remodelling for RA;

To explore the ability of modern anti-rheumatic drugs to intervene with these processes;

To prevent interaction between survivin and its chromatin-bound partners and to reprogram survivin-dependent effects in T cells.

Metod

We collect blood leukocytes sorted into CD4, CD8 and CD14 cells from the pre-RA and early RA patients and submit it to RNA sequencing and DNA methylation analyses.

To study survivin binding to chromatin, we perform chromatin immunoprecipitation (ChIP-seq) using antibodies to survivin and histone H3 modifications H3K4me3, H3K27me3 and H3K27ac in naïve and memory CD4 +T cells. We use genome editing approach to show functional importance of survivin binding to regulatory DNA. We screen peptides to prevent survivin binding to EZH2.

To study effect of MTX, TNFi and JAKi on survivin binding to chromatin, we treat CD4 cells with these drugs prior to ChIP-seq and transcriptomic analysis.

Betydelse för patienten 

Pharmacological treatment of RA lacks reliable tests to personalise the choice of drug, to predict treatment response, and to foresee disease flare. Serum survivin is a reliable biomarker of the processes maintaining the disease. Integration of survivin measure with regular tests in rheumatology awaits. This project will extend the knowledge about survivin-dependent processes and calibrate modern antirheumatic drugs by the ability to intervene with them. This project will combine the NGS and clinical RA data to map pathological gene nodes, which increase precision of drug choice and improve the quality of care for RA patients.