Tissue damage and repair represent fundamental problems in human health. Wound repair involves the integration of complex networks at both the single cell and multi-cellular level. These networks involve changes in gene expression, cell signaling and motility, and/or the physical properties of the environment that must be integrated to allow for wound healing. There remains a significant gap in understanding how different types of cells communicate to integrate a wound healing response. The focus of our research is to understand the basic molecular mechanisms that regulate cell migration and how defects in cell migration contribute to human disease in the context of tissue damage and repair. We have developed the tools to simultaneously image and manipulate epithelial, macrophage and neutrophil responses to localized tissue damage in zebrafish.
Wound healing and regeneration
We are interested in how early signals at the wound (Reactive Oxigen Species [ROS],and calcium) integrate to mediate wound repair and regeneration. In collaboration with LOCI, we are performing real time imaging using Second harmonic generation microscopy to image the relationship between mesenchymal cells, macrophages and neutrophils and collagen during wound healing. We have identified specific pathways downstream of ROS and calcium after tissue injury that mediate wound resolution. We are also investigating how these pathways are different in the context of sterile injury and infection.
Neutrophil and macrophage migration
We are interested in the molecular mechanisms that regulate neutrophil and macrophage migration including the role of Rho GTPase signaling using both in vitro and in vivo tools in zebrafish. A part of this work involves introducing human disease mutations to examine the impact on leukocyte migration. This work involves the use of microfluidic systems in collaboration with the Beebe laboratory. We are also collaborating with the Sluvkin lab on a recently funded UW2020 project using human iPS cell derived phagocytes.
Host pathogen interactions
We have collaborations with other laboratories in the Microbial Sciences building to examine the innate immune response to bacterial and fungal infection. We are particularly interested in how pathogens disseminate and persist in hosts and the role of the innate immune system in this regulation. Key questions focus on the balance between too much and too little inflammation in the context of infection.
Invasion and cancer
The lab is also interested in the migration and invasion of cancer cells. We have projects focused on invadopodia and invasive cell migration. We are particularly interested in cancer as an “unhealed” wound and the role of innate immune inflammation in cancer progression. We are using several cancer models in zebrafish including melanoma, glioblastoma and hepatocellular carcinoma to examine these questions in vivo.
Resolution of inflammation
We were the first laboratory to visualize neutrophil reverse migration. It was a surprising finding that neutrophils migrate away from wounds, in a process called “reverse migration”. Reverse migration mediates resolution of local neutrophil inflammation induced by tissue damage (Mathias, 2006). The idea that neutrophils resolve inflammation by reverse migration (as opposed to neutrophil apoptosis) represented a paradigm shift for the field and has helped to initiate a new area of investigation. However, little is known about how neutrophil reverse migration is regulated or the specific function of reverse migrated neutrophils. Using both in vitro tools (microfluidic systems) in collaboration with the Beebe laboratory and zebrafish we are studying neutrophil reverse migration and how inflammation resolves.