White blood cells do not conduct immune surveillance in certain organs. These organs are termed immunoprivileged. Immunoprivileged organs include the eyes, the testis and the brain, among others. In immunoprivileged organs, cells other than macrophages serve as phagocytes of cell debris. Many diseases affecting immunoprivileged organs involve these resident phagocytes. Furthermore, noxious effects resulting from inflammation of immunoprivileged organs also involve these cells. It is therefore important to understand the mechanisms of the immune response to dead cells triggered by resident phagocytes. We propose to use two immunoprivileged organs in Drosophila melanogaster: the ovary and the brain. The ovaries of flies are immunoprivileged organs where degeneration of the germ line can easily be induced. Once it occurs, somatically derived follicle cells phagocytose the debris resulting from germ line death. The brain of flies is also immunoprivileged and glia remove neuronal cell corpses. Given the genetic tools available in Drosophila, as well the facility of analyzing these organs, makes Drosophila melanogaster a great experimental model for these studies. More specifically, we propose to conduct three different aims to understand the mechanism of cell clearance in immunoprivileged organs.
The first aim will consist of identifying the interactions between two effectors of nurse cell clearance in Drosophila ovaries. More specifically we will determine the relationship between two genes that we have found to act in the clearance process.
The second aim will be to deduce if the same genetic pathway is involved in the clearance of neuronal corpses by glia.
The final aim will be to conduct a genetic screen to identify the negative regulators of the immune response mediated by glia. More specifically we will identify proteins in healthy cells that are involved in this process. Since the mechanisms of cell death and engulfment are highly conserved, these experiments will increase our knowledge of the immune response to dead cells in immunoprivileged organs. It is likely that these findings will have implications in understanding and treating human disease.
Project Narrative Many of the diseases which affect the brain and other organs involve a particular subset of cells which are in charge of removing dead cells from these organs. Understanding how they work can have a great impact on the treatment of disease. This project will investigate how these cells work in a tractable model system.
|Etchegaray, Jon Iker; Elguero, Emma J; Tran, Jennifer A et al. (2016) Defective Phagocytic Corpse Processing Results in Neurodegeneration and Can Be Rescued by TORC1 Activation. J Neurosci 36:3170-83|
|Etchegaray, Jon Iker; Timmons, Allison K; Klein, Adam P et al. (2012) Draper acts through the JNK pathway to control synchronous engulfment of dying germline cells by follicular epithelial cells. Development 139:4029-39|