Mechanobiology of the Endothelial Cell Glyxcocalyx

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Over the past 15 years, my lab has developed unique models and techniques to help understand how cells sense and respond to mechanical forces (mechanobiology). In the next 5 years I will use my NSERC discovery grant to further our investigation into endothelial cell mechanobiology. Recent work has led us to focus on the role of the gel-like layer that covers cells, the glycocalyx (GCX). This delicate sugar-based structure is believed to be a major regulator of endothelial cell physiology. We have shown that enzymatic degradation of the GCX abrogates the natural response of these cells to wall shear stress. We have also observed that endothelial cells in regions of wall shear stress gradients show damage to the GCX. We hypothesize that damage to the endothelial cell GCX can unbalance the natural mechanobiology of cells leading to dysfunction. How cells convert mechanical stress into biological events (mechanotransduction) is poorly understood. Moreover, how the cell regulates the elements that sense these stresses (mechanosensors) is largely undiscovered. The long term goal of the proposed research is to understand the cellular signaling involved in mechanotransduction and how the cell regulates this response by manipulating its mechanosensors. In the next 5 years, my lab will focus on the mechanobiology of the GCX. Specifically, we will use our in vitro models to:******1. Understand how cells regulate their glycocalyx in response to biomechanical forces***2. Identify components of the glycocalyx important to mechanosensing***3. Elucidate signaling pathways linked to glycocalyx mechanotransduction******The research will include experiments designed to impart defined wall shear stress gradients to endothelial cells in vitro. The effect of the mechanical environment on shedding and regrowth of the GCX will be identified. We will also manipulate the composition of the endothelial cell GCX to identify key components and ways to mitigate damage. We will block suspected pathways involved in mechanotransduction by the GCX to unravel intracellular signaling. ******Overall, the work will further our understanding of the fundamental process in cells that allow them to adapt to their mechanical environment. The underlying data obtained will have a significant impact in tissue engineering, drug discovery, developmental biology and pathology. The program will provide an excellent training environment for HQP. It will push the boundaries of science and engineering by developing new models and analysis techniques. Finally, the work will require HQP to work in a multidisciplinary environment, leveraging their engineering background to elucidate the mechanobiology of the GCX.