Atherosclerosis is the most important cause of cardiovascular disease, which is the most common cause of death worldwide. Christian Weber was able to prove that a micro-RNA snippet called miR126-5p can protect against atherosclerosis by binding and inactivating the enzyme caspase-3 in the cell nucleus, which triggers programmed cell death. Weber thus discovered a completely new function of micro-RNAs, which were previously thought to typically act in the cytoplasm and suppress or degrade messenger RNAs in a silencing complex. The new signalling pathway is mediated by the RNA-binding protein MEX3A, which is now the focus of Weber's ERC project MONOFUN-CV.
In his project, Weber is using MEX3A as a starting point to systematically investigate these newly discovered non-canonical miRNA mechanisms with his team. The aim is to investigate the cell-specific functions of MEX3A in atherosclerosis in a mouse model and to identify genetic risk factors in humans by analogy. With the help of various screenings, the researchers want to find further miRNAs whose effect is mediated by MEX3A, as well as other proteins that are directly regulated by miRNAs, and elucidate the structural mechanisms for the function of MEX3A. The project also aims to analyse the direct interactions between miR-126-5p and caspase-3 - including their biological relevance in vivo - and to systematically search for further functional miRNA-protein pairs that can serve as templates for novel RNA-based therapeutics.
In the long term, these findings could provide new insights into non-canonical mechanisms of miRNAs and open up new therapeutic approaches - not only for cardiovascular diseases, but also for other diseases.
Source: Press release of Munich University Hospital
