PROJECT SUMMARY Epithelia are the core cell type of animals, and constitute the most widespread and ancient mode of tissue architecture. My lab uses a distinctive set of multidisciplinary strategies to study fundamental questions of epithelial biology using Drosophila, leveraging deep evolutionary conservation to uncover general principles applicable across phylogeny. The research proposed in this MIRA renewal tackles basic mechanisms underlying epithelial organ shaping and the total body’s response to epithelial injury. Both goals -- one in which we have a long track record and another stimulated by discoveries during the previous funding period-- build on my laboratory’s 20-year NIGMS-funded research program. In one direction we will investigate how developing epithelia respond not just to intracellular forces, but also to resistance from the extracellular matrix. This understudied question is central to the morphogenetic movements that allow organs to attain the specific forms required for function. Our previous work has shown how an organ can be sculpted by finely patterned mechanical properties of the basement membrane that underlies all epithelia. We will determine the mechanisms that regulate conserved matrix components and modifiers to achieve precise mechanical patterning, and then exploit this knowledge to manipulate tissue shape in a predictable fashion. In the other direction, we will explore the whole-body response to epithelial barrier damage. While the local wound response is well-characterized and conserved across many phyla, animals also have systemic wound responses mediated by signaling factors that communicate with distant organs. The mechanisms and impact of these humoral responses, which include but are not limited to inflammation, are poorly understood compared to the antimicrobial immune response triggered in parallel; they may include unappreciated signaling molecules and exotic forms of signal transmission alongside well-known pathways such as TNF. Leveraging the strengths of Drosophila for discovery biology, we will induce sterile injury in adult epithelial tissues and identify signaling axes that communicate between the organ of insult and responding tissues to promote homeostasis and health. This goal will include a comprehensive analysis of TNF signaling in the adult, and investigation of differences between normal tissue repair and that triggered by chronic inflammation. The proposed experiments tackle these key questions by combining the traditional strengths of Drosophila genetics with advanced imaging and new biochemical techniques, empowered by collaborations. Our results will enhance understanding of conserved mechanisms that generate functional epithelial organs during development, and lay the foundation for addressing disorders driven by epithelial damage and pathology.

PROJECT NARRATIVE Epithelia are the core cell type of animals, forming protective barriers that also shape most tissues during development. This project will study underinvestigated mechanisms by which extracellular matrix sculpts organs, defects in which can cause congenital malformations. It will also study how damaged epithelial barriers signal to other organs to help the animal respond systemically to injury, including through the Tumor Necrosis Factor signaling pathway.