Zenith Grant of 500 K Euro for Timothy Radstake scleroderma research

Radstake Tim

Closing in on defective telomere function in systemic sclerosis; novel avenues to predict prognosis and personalize treatment.

Systemic sclerosis otherwise known as scleroderma is a severe condition characterized by exaggerated scar formation in the skin and internal organs such as heart and lungs. Although the scar formation of the skin leads to painful ulcerations at the fingertips, the involvement of heart and lungs severely diminishes patient survival.

Hence, scleroderma is often more fatal than most cancers. The cause of scleroderma is unknown. However, research from our group over the past 4 years has changed our way of thinking about scleroderma drastically. We found that a specific cell type from our immune system is over produced, which is probably caused by a not well function system that normally protects cells against accelerated ageing. In this project, we will use the unique data we have collected over de past years from over 5000 scleroderma cases to determine what genes and proteins underlie this defect. The robustness of our data so far, together with the unique teaming up of very good collaborators, this project is likely to rapidly lead to new therapeutic targets for the treatment of this condition.

And a shortened life expectancy often being more deadly than cancer. Accumulating evidence now suggests the involvement of the immune system in contrast with the 'fibroblasts postulate', were fibroblasts are suggested to have a primary defect leading to over-production of extra-cellular matrix, that was broadly advocated the last decade (1). In addition to this changed vision, we recently demonstrated that plasmacytoid DCs have a markedly altered frequency and biology which prompted us to investigate telomere length and function. We found that telomere length and function are dramatically and specifically altered in certain cellular subsets and clinical phenotypes, which potentially leads to de novo mutations culminating in a vicious circle of immune dysfunction. The current project aims to unravel the genetic and protein pathways that underlie the aberrant telomere biology in SSc by exploiting a unique cohort of SSc patients (n ~ 5000) used for genetic (GWAS) and immune profiling previously. This together with the widespread knowledge on bioinformatics (Prof. Martijn Huynen, CMBI, Nijmegen), protein-protein interaction analysis (Prof. Michiel Vermeulen, UMCU) and telomere biology (prof. P. Shiels, Glasgow) will greatly facilitate the identification of prognostic markers to distinguish patients in need for aggressive treatment from those who have self-limiting disease. Furthermore, a better insight in the circuitry that explains the aberrant function of pDC and/or B cells in SSc will promptly leads to the broadening of our therapeutic armamentarium for this disease.

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