Characterization of regulatory mechanisms mediating microRNA selection, packaging and transfer via microvesicles

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Cardiovascular diseases, such as coronary heart disease, are the leading cause of death worldwide. The underlying pathology is atherosclerosis.The endothelium contains of endothelial cells, which are located at the innermost layer of blood vessels. Endothelial injury leads to endothelial dysfunction, the migration of inflammatory cells into the vessel wall, the development of atheroclerotic plaques, and finally to atherogenesis. To break this pathological signaling cascade after an initial injury, is a better understanding of endothelial repair mechanisms of great therapeutic relevance.Preliminary work has shown that apoptotic endothelial cells release small membrane vesicles, called microvesicles (MVs) or apoptotic particles, into the bloodstream. MVs contain a variety of bioactive mediators (RNA, microRNA, proteins, cytokines), which can be transferred into target cells influencing function and phenotype of the recipient cell.Recent studies have shown that the biological function of MVs mainly depends on the intravesicularly microRNA (miR) expression profile. MiRs are small, non-coding RNAs that control gene expression by binding to mRNA and represent key regulators of vascular hemostasis.Preliminary work has shown that endothelial cell-derived MVs (EMVs) are taken up by adjacent endothelial and circulating progenitor cells, protecting them from apoptosis and stimulating endothelial repair processes. The EMV-mediated transfer of miR-126-3p in recipient endothelial cells and the consecutive inhibition of spred-1 could be worked out as an underlying mechanism of EMV-mediated endothelial regeneration.While there is increasing evidence that miRs in MVs play a crucial role in intercellular communication processes, however, it is largely unclear which factors control the intracellular selection and packaging of miRs into EMVs.A molecular exploration of intracellular regulatory mechanisms of miR selection, sorting and packaging into EMVs represents a key point of the present application. Moreover, the molecular biological effect of miRs transferred by EMVs in target cells will be characterized. Finally, the role of MVs as a transfer and application vehicle for selected miRs will be explored.The planned experiments will contribute to a better mechanistic understanding regarding the biogenesis, the secretion, the composition and the interactions with target cells of EMVs. In the long term, our results could open new diagnostic and therapeutic options to combat cardiovascular disease.