MONOFUN-CV · Modulating non-canonical functions of microRNAs in cardiovascular disease

Atherosclerosis is the major underlying pathology of cardiovascular diseases (CVD), which remain the leading cause of death worldwide. The relevance of miRNAs in vascular biology, atherosclerosis and CVD has been well established. Our discovery of an aptamer-like binding of an endogenous miRNA to proteins, namely that of nuclear miR-126-5p to caspase-3, as facilitated by the RNA-binding protein MEX3A has extended the classical paradigm of miRNA function in the RISC, adding a new layer to the mechanisms enacted by miRNAs. Taking MEX3A as a starting point, MONO-FUN-CV aims to (1) characterize cell-specific contributions of MEX3A to mouse atherosclerosis and an association of MEX3a risk variants with human atherosclerosis, to dissect the specificity of its cross-talk with miR-126-5p, and to unravel potential MEX3A-based therapeutic options; we will (2) conduct an unbiased analysis of miRNAs affected by MEX3A (e.g. by eCLIP), elucidate the structural basis and mechanisms controlling MEX3A functions, e.g. ternary complex formation with AGO2, nuclear shuttling, and involvement of other adaptors (proteins, RNA); and (3) we will clarify structural bases and sequence requirements of miR-126-5p interactions with caspase-3, and its physiological relevance using novel in vivo models, as well as screen other miRNAs and proteins engaging in functional interactions, such as miR-210-5p and HIF-1α, to define templates for novel molecular modulators, e.g. aptamers. All aims include unbiased strategies to discover related miRNAs (e.g. nuclear, MEX3A-interacting) and adaptors contributing to the control of protein functions. These aims are highly interconnected and may enable groundbreaking insights into non-canonical mechanisms of miRNAs and their translation into novel approaches for therapeutic targeting of CVD and beyond.