Physical, molecular, and cellular control of wound closure - Abstract The skin protects animals and humans from harm. To this end, the skin needs to detect and repair wounds. Slowed or failed wound detection and repair causes different skin disorders and signaling pathways that detect and repair wounds are potential targets for clinically important therapeutics. The goal of this project is to identify the pathways and mechanisms that the skin uses to detect and repair wounds. For this, we combine genetics and imaging in zebrafish embryos with computational modeling. Identical to the human embryonic skin, the zebrafish embryonic skin consists of two cell layers – an outer and a basal layer. Due to its transparency, the zebrafish embryonic skin can be imaged at high resolution, which permits quantitative measurements and data-based computational modeling. We have found a G-protein coupled receptor (GPCR) signaling pathway that is activated in the skin cells at the margin of wounds, and we have built tools to image the force-generating and force-transmitting machinery in skin cells. Using these tools, we will address three questions. First, we will decipher how the skin cells use the GPCR signaling to detect wounds. Second, we will ask how the two layers of the skin cooperate to move and close wounds. Third, we will use the quantitative imaging data and measurements of physical properties of the skin to generate a physical model of a two-layered skin that we will test and refine using physical and genetically perturbations. Since epithelial integrity is essential for many organs including the lining of the gut, blood vessels and lungs, the proposed studies will provide necessary context to better understand epithelial barrier function in general and should inform us about strategies of how to correct epithelial disorders.
