PROJECT SUMMARY Signaling mechanisms that control cellular responses to light and UV-induced DNA damage play critical roles in preserving retinal function. The Jasper lab has characterized such signaling mechanisms using the Drosophila retina as a genetically accessible model system to study UV-induced cell death of photoreceptors. In the course of these studies, it has been established that retinal homeostasis is not only maintained by cell autonomous mechanisms, but also by systemic signals, and that retina-associated immune cells (hemocytes) also play a critical role in promoting tissue homeostasis. In mammals, tissue-resident macrophages (or microglia) play an important role in promoting homeostasis of the retina, influencing retinal diseases, including age-related macular degeneration. The signaling mechanisms that govern the interaction between neurons and macrophages, however, are only beginning to be understood, and appropriate genetic model systems to explore these mechanisms remain elusive. The Jasper lab has demonstrated recently that studying innate immune cell interactions with the damaged retina in flies can lead to the discovery of genes and mechanisms that are conserved in the mammalian retina and that can lead to new approaches for retinal therapy. The studies proposed here will extend this work and use the fly system to better characterize the interaction of immune cells with the damaged retina and identify new genes and proteins that mediate this interaction. In new preliminary studies presented here, the applicant has identified additional signaling events, controlled by the BMP-like Dpp signaling pathway, that promise to explain in more detail how hemocytes are activated to promote photoreceptor cell death in response to retinal damage, and how, in a later phase of the damage response, these cells promote tissue repair and regeneration. The applicant proposes genetic studies to (i) characterize the signaling events promoting photoreceptor cell death in more detail, (ii) explore the signaling pathways regulating hemocyte activation and differentiation, and (iii) identify and characterize new genes that modulate these responses. Important technical advantages of the Drosophila system for the study of hemocyte / retina interactions include the ability to perturb gene function with spatiotemporal precision and to characterize resulting phenotypes quantitatively. It is thus anticipated that significant progress can be made in our understanding of signaling mechanisms regulating the interaction between retinal cells and resident macrophages, and of the consequences of this interaction for tissue health. Since the analyzed cellular and molecular signaling mechanisms are widely conserved, it can be anticipated that significant insight can be obtained that will inform our understanding of the control of retinal homeostasis in humans.