Modulating non-canonical functions of microRNAs in atherosclerosis

• Applicant: Professor Dr. Christian Weber
• Subject Area: Cardiology, Angiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 538188320

Atherosclerosis is the major underlying pathology of cardiovascular diseases (CVD), which are the leading cause of death worldwide. The relevance of microRNAs (miRNAs) in atherosclerosis and CVD has been well established. Our discovery of an aptamer-like binding of an endogenous miRNA to proteins, namely that of miR-126-5p to caspase-3, as facilitated by the RNA-binding protein Mex3a has extended the classical paradigm of miRNA function, adding a new layer to the mechanisms enacted by miRNAs. Taking Mex3a as a starting point, this project aims to (1) characterize cell-specific contributions of Mex3a to atherosclerosis in mechanistic studies in mice and analysis of genetic risk variants in humans, 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, elucidate the mechanisms and structural basis controlling Mex3a function, e.g. complex formation with Ago2 and other proteins, nuclear shuttling, and involvement of other adaptors (proteins, RNA); and (3) we will clarify the structural basis and sequence requirements of miR-126-5p interactions with caspase-3, its physiological relevance using novel in vivo models, and identify additional miRNAs/proteins engaging in similar functional interactions to define templates for novel modulators, e.g. aptamers. All aims include unbiased strategies to discover components contributing to non-canonical functions of miRNAs. The aims are highly interconnected and will provide groundbreaking insights into an uncharted field of molecular biology. The high-risk nature and the innovative research field make the Reinhart-Koselleck program the unique suitable funding framework for this project.

• DFG Programme: Reinhart Koselleck Projects