ABSTRACT The overall goal of this Maximizing Investigator’s Research award renewal application is to understand the integration of complex signaling networks at both the single cell and multi-cellular level during wound healing. Despite progress in understanding the signals that guide wound repair, there remains a significant gap in understanding how different types of cells communicate to integrate a wound healing response. This gap limits our ability to design new therapeutic strategies for a broad range of human disease including diabetes, cancer, cardiovascular disease and autoimmunity. The overall 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. The optical transparency and ease of genetic manipulation make zebrafish an ideal model system to dissect multi-cellular and tissue interactions during wound repair. During the prior funding period, we invested significant effort in developing new tools for imaging and manipulating cell dynamics, cell guidance cues, metabolism and matrix remodeling during wound healing in both simple and complex wound models. We performed large-scale TRAP (translating ribosomal affinity purification)- RNAseq and identified context- and cell-type specific gene expression changes. Using genome editing we are now poised to uncover new signaling mechanisms and guidance cues that regulate neutrophil reverse migration and inflammation resolution, and influence matrix remodeling during wound healing. Understanding how wound repair is orchestrated and integrated at both the single cell and multi-cellular level, including the role of microbial interactions, in the different types of tissue damage is the focus of our future research. The overall goal of our work is to identify key signaling networks and guidance cues that mediate cell migration during wound repair, dissect how they are altered in pathological conditions and ultimately may be targeted to understand and treat human disease.

PROJECT NARRATIVE Our work focuses on understanding how inflammation resolves and tissues are repaired in the context of human health and disease. We aim to uncover mechanisms of cell migration within tissues, the signaling networks that regulate these processes and how they are integrated during wound healing. This work will impact our understanding and treatment of autoimmune disease, diabetic and other chronic wounds, cancer and immune deficiency disorders.