Specificity determinants of the cargo content sorted into cell-derived microvesicles

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The normal functioning of multicellular organisms is a complex process, requiring the integration of autonomous cellular activities involving both local and long-range specific intercellular signaling interactions with tissues and organs. Central to this seamless functioning are extracellular vesicles (EVs), specifically, exosomes. Exosomes are small, membrane-bound particles secreted from almost all cell types ranging in size from 30 to 150 nm. Each exosome contains a specific set of nucleic acids, proteins, and lipids. Exosomes can interact with other cells and/or transfer their content to target recipient cells, functionally altering them in precise ways. The ability of exosomes secreted from one cell type to "reprogram" other cells at a distance has been demonstrated in tissue culture. However, the mechanisms leading to the cellular generation of a repertoire of exosomes containing quite distinct and specific biological messages remain unknown. The main objective of this research is to investigate the cell biology of exosome generation focusing on how specific cellular molecules are sorted for loading into exosomes. We have recently shown that infection (Hepatitis C Virus) and cellular stress (Alcohol) can induce cells to release exosomes with quite distinct molecular composition compared to normal conditions. This research program will, therefore, evaluate how infection and cellular stress conditions modulate the qualitative or quantitative changes in proteins, nucleic acids, and lipids contents of cell-released exosomes. Using a combination of virus infection and cell stress experimental models in-vitro, we will additionally decipher and delineate how newly identified specific cellular genes and molecules determine the selection and/ or exclusion of cellular molecules for loading and release inside exosomes. Answering these questions will advance the nascent, rapidly growing field of exosomal cell biology, and expand our understanding of the repertoire of cellular genes and signaling mechanisms used by cells to generate specific exosomes under different circumstances. In addition to providing new knowledge, many aspects of this research will present excellent hands-on opportunities for students and trainees at all levels, and thus can serve as a critical starting point or advancement step for developing careers in fundamental biology or virology.