Measuring the influence of biomechanical forces on biological processes.

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Exposure to biomechanical forces (such as tension, shear stress and pulsatile hemodynamic strain) is essential for normal development of the cardiovascular system, and alterations in force transmission can lead to pathological consequences including kidney and heart disease. The phenomenon by which physical forces are translated into biological responses is called mechanotransduction, and this is regulated via biochemical cues that drive changes in gene and protein expression. To better understand the molecular and cellular signals that are influenced by mechanotransduction, it is necessary to use relatively simple experimental models such as cultures of single cell types. For example, to investigate how an increase in pressure can influence the stiffness of the heart, it is logical to study cardiac fibroblasts as these cells control the level of collagen in the heart. Similarly, to assess how changes in blood pressure and blood filtration influence kidney function, the unique filtering cells of the kidney known as podocytes can be studied. While remarkable strides have been made in growing these unique cell types in static culture, these conditions do not provide the added biomechanical challenge seen in intact organs. The Flexcell FX6000 Tension System requested in this RTI application is a specialized cell stretch apparatus capable of simulating complex in vivo biomechanical forces in simplified in vitro cell culture models. It is the only instrument on the market that allows for controlled multidirectional stretch of cultured cells, mimicking the balloon-like expansion of blood vessels and vascularized tissues. The requested equipment will advance two leading edge research programs at the University of Guelph in eukaryotic cell signalling (Jones) and cardiac physiology (Gillis), and will also be used by a large group of multidisciplinary researchers in cardiovascular science, cancer biology as well as neuroscience on campus. The co-applicants require the Flexcell system to address the following outstanding research questions: 1) How do biomechanical forces influence the adhesive properties of podocytes? 2) How do changes in cell signalling patterns caused by specific genetic mutations lead to podocyte loss? 3) What is the role of biomechanical force is stimulating the migration of neurons and cancer cells? 4) How does a change in blood pressure lead to increased collagen deposition and cardiac fibrosis? 5) What are the cellular pathways involved in reversing cardiac fibrosis in the trout heart? Addressing these questions will provide fundamental insight into the role of biomechanical forces in driving the normal development of complex biological tissues, and how alterations in force transmission lead to tissue dysfunction.