Drosophila, a new genetic model for renal disease and drug discovery

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DESCRIPTION (provided by applicant): We have developed a new system to identify and study genes required for filtration and protein reabsorption in Drosophila. We found that the genes and genetic pathways controlling these two key renal functions are highly conserved from Drosophila to humans, making Drosophila an ideal model to study renal disease genes. Using a novel functional readout that we developed in Drosophila, we performed a large-scale genetic screen and identified ~150 genes required for the function of pericardial nephrocytes, the cell type that functions as insect kidneys. These 150 genes encode proteins in a variety of biological processes and renal specific structures, including slit diaphragm components, glomerular basement membrane components, membrane receptors, actin cytoskeletons, TRP channels, vesicle trafficking molecules, myosin and dynein motors, transcription factors and the Coenzyme Q (CoQ) biosynthesis pathways. Most of these genes are highly conserved from Drosophila to humans and many have human homologues that have already been linked to renal disease, particularly glomerular diseases. Mutations of four CoQ pathway genes have been linked to renal disease and their fly homologues were identified from our nephrocyte screen. Coenzyme Q10 is the final product of the CoQ pathway and a common dietary supplement. The renal functional defect in human patients with COQ2 mutations can be successfully treated with Q10. We proposed to develop fly renal disease models to recapitulate the human COQ gene mutations that cause renal disease, and to treat these fly disease models with Q10, to provide a proof-of-principle for our new fly renal disease models with a drug treatment approach. We will then apply this approach to study the pathogenic mechanism of novel renal disease genes RhoGDIa and KANK2, and test potential drugs for the fly models of renal disease caused by mutations of these two genes. In summary, this proposal introduced a new animal system to study renal disease genes and an innovated approach to develop animal disease models for testing drugs. Given the promising findings and solid evidence for the conserveness of renal disease genes from Drosophila to humans, we believe that this new fly system will provide the means to study pathogenic mechanisms of renal disease caused by specific gene mutations, and to discover clinically relevant drugs that could eventually lead to cures for these currently untreatable renal diseases.