Project Summary Cell death is a fundamental process in animal development and homeostasis. Misregulation of cell death is associated with a large number of human diseases. Our research program aims to understand the diverse mechanisms of cell death, how dead cells are efficiently removed, and the physiological effects on organisms when these processes go awry. We study these questions in Drosophila, a model organism with exceptional genetic, genomic and cell biological tools. Our research program focuses on several major projects. The first project investigates non-apoptotic cell death which contributes significantly to development and disease, but is poorly understood. In the Drosophila ovary, germline-derived nurse cells undergo non-apoptotic programmed cell death as part of normal development. We have found that nurse cell death is controlled largely non-autonomously by the surrounding somatic follicle cells by phagocytic and lysosomal proteins. Ongoing work will uncover the subcellular mechanisms controlling nurse cell destruction. A second major project investigates how dead cells are removed, particularly in tissues without access to circulating phagocytes such as macrophages. In many mammalian tissues, dead cells can be cleared by epithelial cells. In a Drosophila model for engulfment by epithelial cells, starvation induces degeneration of egg chambers, where the germline is engulfed by the surrounding epithelial follicle cells. This engulfment process happens synchronously and rapidly at the onset of cell death; however, the genetic requirements for engulfment by epithelial cells are not well understood. In particular, how such non-professional phagocytes increase their phagocytic capacity is not known. Our research program is revealing how epithelial cells transform to a phagocytic state and how they act to promote cell death. A third project addresses the consequences of defective phagocytosis in the brain which we have found leads to neurodegeneration and immune activation. Future work will investigate the links between phagocytosis, immune signaling and neurodegeneration. We will determine the cell- type-specific responses to defective phagocytosis and susceptibility to neurodegeneration. A fourth project investigates cross-tissue interactions in response to cell death in the maintenance of homeostasis. Given the high degree of conservation of cell death mechanisms between Drosophila and mammals, we expect that pathways that we uncover in the fly will provide insight into the diversity of cell death mechanisms and consequences of defective cell removal in humans.