Analysis of conserved pathways involved in maintaining homeostasis and survival in mammals and Drosophila. (360G-Wellcome-094879_A_10_Z)

Our aim is to uncover the molecular basis for toxin clearance from animal body fluids. Using a simple tissue, nephrocyte cells, in Drosophila as a model for blood filtration and detoxification in vertebrates we focus on two molecular pathways essential for these functions; Ig domain proteins (Nephrin, Neph1) required for construction of the podocyte filtration slit diaphragm and the cytoplasmic protein (Rudhira), essential for the micropinocytotic activity in reticulo-endothelial cell scavenger s. Drosophila homologues of these proteins are expressed in nephrocytes. Our goals are to exploit ongoing Drosophila screens to identify candidate molecular interactors to establish the protein interactions that regulate the activity of these pathways, to analyse the roles of identified protein networks in nephrocyte filtration and toxin clearance and to extend our analysis into vertebrate tissues. We aim to test vertebrate homologues for conservation of the molecular interactions identified in Drosophila and, using podocyte cell lines and mutant mouse strains to establish the roles of Ig domain and Rudhira interactors, focussing on podocyte filtration. Overall we shall identify molecular activities that are fundamental to the stability and function of the slit diaphragm and for regulated endocytosis and vesicle trafficking.