Professor Christian Weber is Director of the Institute for Cardiovascular Prevention at the LMU Hospital, as well as Chair of Preventive Vascular Medicine and a member of the SyNergy Cluster of Excellence.
Atherosclerosis is the most important cause of cardiovascular disease, the leading cause of death worldwide. Christian Weber was able to demonstrate that a microRNA snippet called miR126-5p can protect against atherosclerosis by binding to and inactivating the enzyme caspase-3 in the cell nucleus, which induces programmed cell death. Weber thus discovered a completely new function of microRNAs, which were previously thought to typically act in the cytoplasm and suppress or degrade messenger RNAs in a silencing complex. This new signaling 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 and his team are using MEX3A as a starting point to systematically investigate these newly discovered non-canonical miRNA mechanisms. The goal is to explore the cell-specific functions of MEX3A in atherosclerosis using a mouse model and, by analogy, to identify genetic risk factors in humans. Using various screening approaches, the researchers aim to identify additional miRNAs whose effects are mediated by MEX3A, as well as other proteins directly regulated by miRNAs, and to elucidate the structural mechanisms underlying MEX3A function. The project also aims to analyze the direct interactions between miR-126-5p and caspase-3—including their biological relevance in vivo—and to systematically search for additional functional miRNA-protein pairs that could 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 clinical conditions.
