Regulation of wound detection in animal tissues

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Project Summary Wounding of epithelial tissue barriers disrupts homeostasis and allows infection. Within minutes, tissues detect injury and respond by recruiting phagocytes and closing the barrier breach. The signals that activate these early events are scarcely known, and our overall aim is to identify them. We have used zebrafish, whose wound responses are close to mammals and easy to image and perturb with genetics and pharmacology, to define early wound signals. During the last grant cycle, we found that activation of Duox, an H2O2-producing NADPH-oxidase, and release of a lipid chemoattractant (5-KETE), together are required to attract leukocytes to epithelial wounds. The molecular mechanisms that integrate NADPH-oxidase activity with lipid chemoattractant production remain unclear. In parallel, we identified extracellular ATP (eATP) as crucial paracrine mediator of rapid wound closure through stimulating basal epithelial cell migration in vivo. The molecular mechanisms that convey ATP release and sensing to promote epithelial repair remain unclear. For the following grant cycle, I propose to investigate how Duox activity regulates lipid chemoattractant production, and how eATP is released and sensed in live tissues to mediate rapid epithelial repair. By combining real-time biosensor imaging in live zebrafish with genet- ics, bioinformatics, biochemistry and chemical biology approaches, we aim to identify and characterize elusive molecular key players of wound detection in vivo. Our research has strong potential to provide new drug targets for anti-inflammatory and anti-fibrotic therapy.