Monday, January 13, 2025
1/13/2025
Project Summary Maintaining epithelial homeostasis is crucial for organismal health since its disruption is linked to multiple human diseases, such as cancers. Cells elicit many behaviors to maintain the structure and function of epithelia during normal homeostasis and stress. Comprehending their behavior is essential for promoting our knowledge of how to keep epithelia healthy. We propose to take advantage of the robustness of the Drosophila intestinal system to gain new insights into complex cell behaviors that remain understudied. Our R35-funded research concerns `cell extrusion', a process that removes unnecessary, defective, or potentially harmful cells from epithelia without disrupting its barrier function. Over the past five years, we established the Drosophila intestine as a new model for studying how intestinal epithelial cells expressing an oncogenic Ras (RasV12) are eliminated apically and basally from the intestinal epithelium. We have identified multiple new players in the process and provided new concepts to the field. Moreover, our study resulted in two new observations: 1) Drosophila macrophage-like immune cells hemocytes infiltrate into the intestinal epithelium and elicit complex cell behaviors under stress, and 2) intestinal epithelial cells generate long-range projections, resembling `airinimes'—structures that mediate long-distance signaling during pigment development in zebrafish. These cell behaviors are documented in multiple model systems; however, their physiological significance and underlying molecular mechanisms require additional investigation. Our observations bring an exciting opportunity to leverage the powerful genetic tools available in Drosophila to understand the roles of these cell behaviors in a native context and identify new players in these processes. Thus, we propose to expand our research scope to include these additional complex cell behaviors. Continuing our work on cell extrusion, we will focus on addressing what drives the elimination of RasV12-expressing intestinal epithelial cells from the intestine. Regarding the behavior of hemocytes, we propose to investigate how hemocyte-mediated cell behaviors contribute to the maintenance of the intestinal epithelium structure and function during normal homeostasis and under stress. Lastly, we will study what signaling is mediated by the long-range projections and what roles they play in the maintenance of intestinal epithelium. The overarching goal is to increase our general understanding of complex cell behaviors underlying epithelial homeostasis by elucidating their biological significance and discovering their molecular mechanisms. These proposed studies will help us to learn the principles that keep epithelia healthy and prevent diseases associated with abnormalities in epithelial homeostasis.
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