Identification and the role of stress-activated molecular pathways in cell adaptation during**microbubble-coupled sonoporation

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MD Precision Inc. is a Canadian company that develops and manufactures ultrasound equipment for clinical**use, including medical imaging. MD Precision Inc. is looking to develop new devices and/or strategies that**couple ultrasound with microbubble-based sonoporation to kill solid tumours. In this process, microbubbles,**which are inert gas-filled lipid shells, are injected into the bloodstream and then subjected to a local ultrasound**field, which makes microbubbles in that field rapidly vibrate. These vibrations generate fluid "micro-jets" that**puncture the plasma membrane of nearby cells. Depending on the size and number of pores, cells either die,**internalize larger doses of drugs, or survive the assault. Overall, microbubble-coupled sonoporation imposes a**strong physical stress on cells. However, cells have evolved multiple molecular pathways that sense various**stresses like membrane damage. Ultimately, the goal of these stress-activated pathways is to alter gene**expression and/or protein function to adapt surviving cells to stress and improve survivability during**subsequent assaults. It is not known if and which stress-sensing pathways are engaged during the physical**stress imposed by microbubble-induced sonoporation and if surviving cells become stress-adapted. In this**project, my laboratory will use Western blotting, flow cytometry and ELISA assays to identify which**stress-activated pathways are engaged during microbubble-sonoporation in normal and transformed cell lines.**We will then use cell proliferation assays to examine if surviving cells become stress-adapted and better**survive subsequent assaults such as exposure to DNA-damaging agents. Finally, we will employ cell**proliferation assays to investigate if co-application of inhibitors of stress-activated pathways during**sonoporation neutralize stress adaption. This new fundamental knowledge of how cells respond and adapt to**physical stress imposed by microbubble-coupled sonoporation will help MD Precision Inc. to innovate**strategies that use microbubble-coupled sonoporation to more effectively destroy tumours. If successful, this**would position MD Precision Inc. to expand its market share, increase its labour force and benefit Canadians.