Wound detection and healing present consecutive steps of a dormant morphogenetic program to restore barrier function and tissue homeostasis after injury. Leukocytes detect a wound within seconds from hundreds of micrometers away, and migrate to the wound within minutes. The mechanisms that spatially propagate the information on where and when an injury has occurred in a tissue remain little studied and understood. By coordinating the behavior of different cell types in the wounded tissue (incl. leukocytes, endothelial and epithelial cells), these mechanisms control length- and time- scales of inflammatory responses, and warrant that duration and amplitude of inflammatory events (e.g. vasodilation, leukocyte recruitment, etc.) scale appropriately with the extent of tissue damage. Using the zebrafish tail fin wounding assay, we recently found that the epithelial NADPH oxidase DUOX generates a gradient of hydrogen peroxide (H2O2) that extends up to ~200 um from the wound margin into the tissue. This gradient is required for rapid wound recruitment of leukocytes. However, it remains still unclear how a reactive chemical such as H2O2, which exhibits little molecular target selectivity and that can damage cells, is harnessed as a specific wound signal. We hypothesize that within tissues, the precise spatial and temporal control of H2O2's range of action and/or cell selectivity allows it to act as a specific signal. To understand how H2O2 mediates wound detection, we thus propose to investigate where and when H2O2 is generated, how far and fast it propagates through the tissue, and where, when, and via which signaling pathways different cell types respond to it. The zebrafish tail fin wounding assay represents an excellent vertebrate model system for imaging wound responses and for molecular perturbation by pharmacology and reverse genetics. To systematically address temporal and spatial dynamics of wound responses, we will use transgenic zebrafish with ubiquitous, endothelial, epithelial, and leukocyte specific expression of fluorescence reporters for H2O2, its likely upstream activator calcium (Ca2+), and downstream effectors NF?B. Using biosensor imaging and molecular perturbation in live zebrafish, we will address fundamental questions of how far and fast H2O2, a novel paracrine signal, travels in tissues, and how this oxidizing chemical is able to mediate specific cellular responses. Further, we will interrogate how length and timescales of H2O2 patterns are regulated by the DUOX activator Ca2+. Finally, we will deduce pathways that cooperate or act downstream of H2O2 from their transcriptional signature using microarray/bioinformatics. Starting with NF?B, a central inflammatory regulator, we will image the spatiotemporal activation of these pathways, and probe their regulation by the H2O2 gradient.
The proposal investigates how animal tissues detect when and where they are wounded, and how they trigger appropriately directed, timed and scaled inflammatory responses accordingly, such as rapid recruitment of white blood cells from nearby blood vessels. Understanding the signaling circuitry that underlies white blood cell recruitment to injury sites will help to better understand the pathologic deregulation of inflammatory events during hyper-inflammatory disease and cancer. This can lead to novel treatments for these conditions.
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