Non-coding RNAs (e.g. micro-RNAs) function as relevant signaling molecules in controlling cell fate. Since these molecules are loaded into extracellular vesicles (exosomes), they also deeply impact cell-to-cell communication.
This project builds on our previous results published in Santangelo et al., Cell Reports 2016: in this work we demonstrated that a conserved extra seed sequence shared by a subset of miRNAs enriched in hepatocyte-derived exosomes has a crucial role in the regulation of their exosome sorting (by means of direct interaction with the RNA-binding protein SYNCRIP).
We deem that it is possible to convey the conceptual advantage resulting from these data into innovative strategies establishing ncRNAs as tools for targeting relevant transcripts in counteracting different cellular processes (e.g. tumor progression).
Specifically, the identification of a molecular mechanism controlling exosomal sorting of specific miRNAs paves the way for the design of chimeric miRNAs that specifically impact the exosomal informational content. We hypothesize that the engineering of specific miRNAs to be loaded into exosomes will magnify their delivery and therefore their biological function.
The experimental design is drawn to: i) provide proof of concept of the transferability in the development of novel therapeutic RNA-based strategies; ii) expand basic current knowledge in the field, therefore pinpointing more therapeutical tools and targets and iii) validate the results obtained to challenge a general value for the ncRNA-based approach.
The expected results include:
i)In vivo exosome-mediated delivery of antifibrotic chimeric miRNAs.
ii)Further exosome-sorting machinery characterization to expand the possibility of a exosomal miRNAs content control.
We expect to extend the basic knowledge on the molecular machinery controlling miRNA sorting in exosome and validate the possibility to in vivo specifically sort in exosome chimeric miRNAs embedding the hEXO motif.
