Grant: Project Grant

Exosomes are extracellular vesicles that are released from living cells under a variety of circumstances. In this proposal we seek to manipulate and engineer these vesicles to carry anti-viral cargo, utilizing altered cellular systems to generate biocompatible exosomal therapeutics that contain small ribonucleic acid (RNA) molecules called microRNAs. MicroRNAs contain small stretches of genetic material that act as regulators to control nearly all human genes. MicroRNAs also can cause chronic diseases such as atherosclerosis and cancer. MicroRNAs such as microRNA-185 are involved in immunometabolic responses to virus infection (the bodies metabolic responses to infection) and have antiviral properties. Little has been done to study secreted microRNAs within extracellular vesicles including exosomes. We propose to study the levels of microRNAs secreted during viral infection and the bodies responses to these infections to identify pro-and anti-viral circulating miRNAs. We also propose to develop new methods for controlling microRNA levels to create new therapeutic exosomal agents. This project aims to study microRNAs secreted by cells infected with positive stranded viruses like Dengue, Zika, and hepatitis C viruses and stimulated immunometabolic responses to infection. Based on these data we will then develop new biological agents that control the microRNA content of extra-cellular vesicles called exosomes, in particular virus infection/disease treating microRNAs. The latter will be based on engineered forms of an RNA binding protein that can bind to human microRNAs. These will be used to control the levels of microRNAs and inhibitors within secreted exosomes from cell culture. The therapeutic potential of these exosomes will be evaluated in cell and mouse models. Long term suppression of microRNA function will be validated in these cells other models for infection to towards the development of broad spectrum antiviral therepeutic exosomes.