Genetic mutations are major causes of renal disease, but the underlying mechanisms of many renal diseases caused by specific mutations remain largely unknown. A highly efficient model system that could be used to identify renal genes, to recapitulate disease-causing genetic mutations, and to serve as a primitive drug testing platform will be highly valuable and significant for the renal disease research field. We have developed a genetic screen for renal function in Drosophila, and identified hundreds of genes required for filtration and protein reabsorption. Most of these genes are highly conserved from Drosophila to humans, and many of them have been linked to renal disease. These 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. Our findings demonstrated that the genetic control of key renal function such as filtration and protein reabsorption is evolutionarily conserved and Drosophila can be used as a model system to study the genetic mechanism of renal disease. The goal of this proposal is to develop specific renal disease models using Drosophila and to establish Drosophila as a primitive drug testing platform for specific genetic renal disease.
In Aim 1, we will use the CoQ pathway as a proof-of-principle to demonstrate the efficiency and feasibility of the new model to identify novel genes required for renal function, to generate the exact recapitulation of human disease mutations, and to test a known drug that could cure specific genetic renal disease in Drosophila.
In Aim 2, we will study the disease mechanism of two novel renal genes (RhoGDI and KANK2) that were both identified from our genetic screen and the human patient exon sequencing from our collaborator. We will generate Drosophila renal disease models for these novel genes and test a collection of chemical inhibitors to identify a potential drug to treat patients with genetic mutations in related pathway. The set of experiments outlined in this proposal have broad significance not only for understanding and treatment of these specific rare genetic renal diseases, but also could be highly applicable to any kinds of renal disease with a genetic cause.
Genetic mutations cause renal diseases, but the underlying mechanisms remain largely unknown, and a highly efficient animal model system for genetic and drug screen is lacking. We have developed Drosophila as a new model for renal disease and showed that the genetic control of key renal functions is highly conserved from Drosophila to humans. The study in this proposal will establish Drosophila as a new genetic model system for renal disease and a new platform for drug testing and screening for genetic renal disease.