Mechanisms governing the midbody remnant in intercellular RNA communication

About This Grant

SUMMARY Cell-cell communication is essential for coordinating complex biological processes, and extracellular vesicles (EVs) have emerged as critical mediators of intercellular signaling. This project focuses on a unique class of large EVs called midbody remnants (MBRs), which are released during cell division. MBRs represent a novel mode of intercellular communication with potential implications in various physiological and pathological contexts. The overarching goal is to elucidate the mechanisms by which MBRs facilitate the transfer of information between cells. Specific goals over the next five years are to: 1) investigate how the informational content of MBRs varies in different biological contexts by identifying and characterizing conserved and unique molecular cargo (RNAs, small RNAs, and cell surface proteins) of MBRs from different cell types, including cancer, stem, and differentiated cells, and 2) elucidating the mechanisms by which recipient cells recognize and internalize MBRs. In addition, 3) we will investigate the potential hijacking of the MBR pathway by viruses for transmission, by examining viral RNA localization, factors required for viral RNA targeting to MBRs, and the ability of virus-infected MBRs to induce infections. Lastly, we will begin to: 4) investigate the role of MBRs in neurodevelopment and neurodevelopmental disorders, like autism spectrum disorder, by profiling changes in MBR informational content during neural progenitor cell differentiation and mechanistically testing genes necessary for cell fate and proliferative function that we find altered or loss in diseased states. The research design involves isolating MBRs from diverse cell types, performing transcriptomic and cell surface proteomic analyses, functional perturbation studies, live-cell imaging, and utilizing cellular and biochemical tools. This interdisciplinary approach will provide mechanistic insights from the genome- wide scale to sub-micron resolution. The findings from this project have significant implications for public health, as they could unravel the roles of MBRs in cell proliferation, RNA signaling, and EV biology, which are crucial in cancer, stem cell biology, and diseases associated with aberrant cell division and proliferation. Furthermore, understanding MBR function may identify novel therapeutic targets and establish MBRs as potential delivery vehicles for treating various diseases.