Project

The role of TNF Receptor-1 regulating microRNA's in inflammation

Duration
01 January 2014 → 31 December 2019
Funding
Research Foundation - Flanders (FWO)
Research disciplines
  • Natural sciences
    • Other biological sciences
Keywords
microRNA's Inflammation TNF Receptor-1
 
Project description

Inflammation lies at the basis of many diseases, such as arthritis, but also multiple sclerosis and certain cancers. We are interested in systemic inflammatory response syndrome (SIRS), an acute inflammatory condition occurring e.g. in sepsis. The cytokine TNF is a master regulator of inflammation and a well-validated drug target. Successful TNF-inhibiting drugs are used to treat several inflammatory diseases, but the big group of non-responders and the side effects leave room for improvement. Our research shows that the major TNF receptor, TNFR1, is a much more specific drug target, but almost nothing is known about the regulation of the TNFR1 on the genetic level. Our recent work demonstrates that small reductions in TNFR1 availability lead to drastic protection in SIRS and that TNFR1 expression in liver and small intestine are most essential in SIRS. We found that miR-511 is a crucial regulator of TNFR1 expression and that there is an clear link between TNFR1 and anti-inflammatory glucocorticoids (GCs). 1. We will go into the details of miR-511 and study it expression pattern, regulation in inflammation and by GCs, generate knockout and over-expressing mice and study its therapeutic niche. 2. We will identify other TNFR1-regulating miRs by predictions, screenings and functional work. 3. We will study the link between TNFR1 regulation and GCs and evaluate whether part of GCs anti-inflammatory effects are due to TNFR1-downregulating miRs induced by dimeric GC receptors.