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.
The proposal investigates the mechanisms by which animal tissues detect that they are wounded and by which they mount rapid protective immune and repair responses. Understanding the signaling circuitry that underlies white blood cell recruitment and epithelial remodeling after injury will help to better understand the pathologic deregulation of inflammatory and repair events during hyper-inflammatory and fibrotic diseases and cancer. This may lead to novel treatments for these conditions.
| Niethammer, Philipp (2018) Wound redox gradients revisited. Semin Cell Dev Biol 80:13-16 |
| Huang, Cong; Niethammer, Philipp (2018) Tissue Damage Signaling Is a Prerequisite for Protective Neutrophil Recruitment to Microbial Infection in Zebrafish. Immunity 48:1006-1013.e6 |
| Enyedi, Balázs; Niethammer, Philipp (2017) Nuclear membrane stretch and its role in mechanotransduction. Nucleus 8:156-161 |
| Jelcic, Mark; Enyedi, Balázs; Xavier, João B et al. (2017) Image-Based Measurement of H2O2 Reaction-Diffusion in Wounded Zebrafish Larvae. Biophys J 112:2011-2018 |
| Enyedi, Balázs; Jelcic, Mark; Niethammer, Philipp (2016) The Cell Nucleus Serves as a Mechanotransducer of Tissue Damage-Induced Inflammation. Cell 165:1160-1170 |
| Niethammer, Philipp (2016) Neutrophil mechanotransduction: A GEF to sense fluid shear stress. J Cell Biol 215:13-14 |
| Enyedi, Balázs; Niethammer, Philipp (2016) A Case for the Nuclear Membrane as a Mechanotransducer. Cell Mol Bioeng 9:247-251 |
| Huang, Cong; Niethammer, Philipp (2016) Illuminating Phagocyte Biology: The View from Zebrafish. Dev Cell 38:133-4 |
| Niethammer, Philipp (2016) The early wound signals. Curr Opin Genet Dev 40:17-22 |
| Jelcic, Mark; Niethammer, Philipp (2015) Do not scratch that mole! Trends Immunol 36:503-4 |
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