Nephrotic syndrome (NS) is one of the most frequent causes of End-Stage Renal Disease (ESRD) in children and young adults, but effective treatment is lacking, particularly for Steroid-Resistant Nephrotic Syndrome (SRNS). Rapid advances in DNA sequencing technology have led to the identification of large numbers of genetic variants that are potential causal factors for SRNS. However, lack of in vivo functional data for these candidate SRNS genes and their variants make it difficult to validate their roles in causing the disease. An animal model that carry the exact mutation found in patients for disease mechanism studies and testing of potential targeted therapies is in great demand. We have established a low-cost, high-efficiency Drosophila model system to generate essential functional data for candidate NS genes and variants, and to expedite the identification of novel NS genes. This novel kidney disease model system exploits the remarkable molecular, structural and functional equivalencies of Drosophila nephrocytes and human podocytes. We studied 40 known NS genes in nephrocytes and found that 85% of these genes play conserved roles in kidney cells from flies to humans. We also discovered underlying disease mechanisms by generating personalized fly NS models in which endogenous fly genes were functionally replaced by human homologs carrying patient-derived mutations. We also developed drug testing platform using these fly NS models, and successfully reversed the renal phenotype using targeted therapy informed by disease mechanism. In this renew proposal, we will use the powerful genetic tools in Drosophila to identify new renal genes involved in autophagy and cytoskeleton regulation. We will identify new nephrocyte cytoskeleton markers and components. We will also develop new personalized Drosophila models for candidate NS genes and novel genetic variants for known NS genes, as well as using the fly models to test potential targeted therapies. Our studies will provide the kidney disease research community with a low-cost high-efficiency model system to functionally validate NS associated genes and genetic variants, to identify novel NS genes, and to develop mechanism-based targeted therapies.
Steroid-resistant nephrotic syndrome is a severe and significant form of kidney disease for which effective treatment options are lacking. Mutations in numerous genes involved in diverse processes are associated with the disease. The ability to identify causal genetic mutations in order to develop targeted therapies based on disease mechanism is essential. We developed a highly efficient Drosophila model system that enables identification and validation of genes and mutations causing steroid-resistant nephrotic syndrome, facilitates study of disease mechanisms, and provides a platform to test potential targeted therapies.
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