The molecular and genetic bases of diverse tissue repair responses in postembryonic Drosophila

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Tissue damage responses are essential for multicellular organisms that occasionally encounter a hostile environment. These multi-tissue responses include epithelial barrier repair (wound healing), inflammation, and sensory responses like nociceptive sensitization. Together, these coordinated responses restore tissue functionality and/or protect the tissue from further damage while it heals. Our overarching hypothesis is that the biology of tissue repair arose early in the evolution of multicellular organisms. Consequently, many of the cellular strategies, signaling pathways, and behaviors that animals use to sense and to repair damage are ancient and evolutionarily conserved. Discovery of the basic cell biology and genetic underpinnings of these damage-induced responses is essential. Our long term goal is to identify the full suite of cells and genes that initiate and execute each tissue damage response and understand how these cells and genes function and work together to orchestrate successful repair of damaged tissues. My laboratory has pioneered the use of Drosophila larvae to study postembryonic tissue damage responses including wound closure, inflammation, and injury-induced nociceptive (pain) sensitization. During our first four years of MIRA funding we discovered important principles of wound edge adhesion dynamics, found a signaling pathway (related to vertebrate Vascular Endothelial Growth Factor [VEGF] signaling) required for spreading of inflammatory blood cells at wound sites, and explored injury-induced sensitization to cold, chemical, and mechanical stimuli. Our work over the next five years will focus on three key questions that emerge naturally from these prior studies: 1. How are adherens junction proteins (like β-Catenin) removed from the wound edge and how does this removal impact other wound-edge responses like actin polymerization? This question emerges from our observation that β-Catenin is rapidly removed from wound-edge membranes. With new tools we developed in the prior grant period we are in an excellent position to image this process in real-time at highly symmetric wounds and to discover which signaling pathways coordinate removal. 2. One key question with respect to inflammation is how inflammatory blood cells initially adhere to the wound. In our second project we will explore this key question and investigate the relationship between immune cell adhesion/spreading and immune cell function at the wound site. Our final project will seek to identify key functional downstream genes that mediate acute injury-induced nociceptive sensitization. This is a major gap in our understanding of this process and a key question in the study of nociceptive sensitization. My lab’s substantial history of creative high-impact research on diverse tissue damage responses suggests strongly that we will continue to make original strides and discoveries, especially if our ongoing grant-writing burden is lessened through the MIRA mechanism. Our system complements others in the field and the likelihood of continued novel basic insight into how organisms cope with tissue damage at the cellular and molecular/genetic levels is high.