As molecular links between mechanosensors and the regulation of cellular processes Rho proteins have a critical position in mechanotransduction. Interestingly during cardiovascular disease (CVD) involving aberrant hemodynamic forces Rho proteins are activated. How do mechanical forces regulate Rho proteins? How do they contribute to the mechanical adaptation of the cell? And How is this mechanism altered during CVD? To answer these questions we have designed a proposal in two phases with interdisciplinary approaches including biochemical assays, three dimensional force microscopy (3DFM) and in vivo analysis. 1.Outgoing phase: To determine how mechanical forces activate Rho proteins and to evaluate the involvement of Rho proteins during the mechanical adaptation to force. We will identify the mechanism of Rho proteins activation using an innovative biochemical assay developed in the host lab and we will evaluate their involvement in mechanical adaptation of the cell using 3DFM. 2.Return phase: To evaluate the pathophysiological relevance of the mechanisms identified during the first phase. We will determine the cellular functions downstream of the regulators identified during phase 1 and we will investigate their activities in two animal models of altered hemodynamic forces by using the small animal physiology core facility available in the return host. The proposed project will yield new insights in different areas of life science from fundamental cell biology to potential identification of new therapeutic targets. First the anticipated results will contribute to better understand how the cells modify their mechanical properties in response to force. This crucial mechanism is central in many aspects of biology. We will also evaluate the modulation of Rho regulators in animal models of CVD; this will permit identification of new pharmacological targets for this public health problem.
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