Determining the biochemical mechanism of microbubble-mediated vascular permeability

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One of the most exciting advancements in targeted drug delivery has been the use of ultrasound and microbubbles as a tool to cause blood vessels become leaky, allowing therapeutics to leave circulation at specific sites in the body. Microbubbles are a small (1-4 um), vascular restricted ultrasound contrast agent that consists of a lipid shell surrounding a gas core. When microbubbles come into contact with a focused ultrasound beam, they begin to expand and contract. Through some unknown biochemical mechanism, expansion and contraction of microbubbles causes the junctions in between the cells that make up the vasculature to break down for a short period of time, likely through the application of physical force. My goal is to develop a natural sciences and engineering research program based on determining what is the biochemical mechanism of how microbubbles can cause the vasculature to become leaky. It is my hypothesis that the rapid expansion and compression of microbubbles applies a physical strain to the vasculature, effectively stretching it and activating proteins that monitor and respond to mechanical stress. My trainees and I will investigate this by designing microbubbles and activating them with specially designed ultrasound pulse sequences within normal mouse vasculature. We will then investigate what gene networks are activated in the vascular endotheilal cells, observe changes in protein localization and activation, and step by step understand how cell signaling changes the vasculature response to expanding and contracting microbubbles. Once we understand this biochemical mechanism in normal vasculature, we can use it as a tool and apply it to other natural sciences and engineering fields, including leukocyte migration, where little is known about the role physical force applied to the vasculature plays. This funding will lead also result in the training of a minimum of 11 HQP within the next 5 years and provide them with an important and novel skillset (cell biology and ultrasound engineering) allowing them to become leaders of innovation within Canadian research.