Piezo mechanosensitive receptor interplay with tight junction proteins for maintenance of epithelial cell number and integrity

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Considering Piezo proteins as mechanoreceptors with a crucial role in physiological cell extrusion and division, the aim of our project will be to translate these findings into mammals and provide a mechanistic description of their interaction with cytoskeleton and tight junction proteins. We will then study molecular mechanisms dependent on Piezo detection of mechanical forces playing a role in intestinal epithelial turnover in vivo, by taking advantage of mouse experimental models. Based on this hypothesis, the specific scientific aims of the present project are as follows:1. Describe the role of Piezo1 for intestinal epithelial turnover in vivo. 2. Determine the relevance of Piezo1 for cell shedding as a process avoiding the accumulation of epithelial cell numbers. 3. Determine the relevance of Piezo1 for cell division as a process to replenish the intestinal epithelium. 4. Characterize Piezo-regulated molecular pathways in the human and murine gut in physiological conditions, with special focus on cytoskeleton and TJs. We will contribute to the mechanistic knowledge about the function of a recently identified molecule which is able to sense mechanical forces (Piezo1), and the downstream pathway which mediates signal transmission to the cytoskeleton and TJs proteins (Rho GTPases).Taken together, our project will provide innovative knowledge on mechanical force sensations and intercellular junctions as regulators of epithelial turnover in the gut, in the context of homeostasis and pathology.