African Americans face elevated risk of kidney disease, due in large part to inheritance of APOL1 risk alleles (RA). The molecular and cellular mechanisms underlying APOL1 nephropathy are being extensively investigated, but the mechanism remains unclear and potential therapeutic targets remain hidden. We generated a Drosophila model to study APOL1 nephropathy and showed that APOL1-RA led to renal cell injury in nephrocytes, the insect structural and functional homologs of human podocytes. The recently developed mouse APOL1 model provides a critical tool to study the molecular mechanism of APOL1 nephropathy and to test promising treatments, but it cannot be used to conduct large-scale genetic screens to identify modifier genes that could antagonize the renal toxicity of APOL1-RA. It is also extremely difficult to use the mouse model to screen for hundreds of candidate drug compounds. The Drosophila system presents unique advantages in terms of low-cost and high-efficiency, making it an ideal model for modifier genetic screening to identify novel APOL1-RA interacting factors that could rescue APOL1 renal toxicity, or to test hundreds of drug compunds identified from cell-based APOL1 drug screens. We propose the following three aims to exploit these unique advantages of Drosophila for APOL1 nephropathy studies: Aim 1, Identify downstream genes of APOL1-RA using RNA-Seq and cross-species comparison, and test them as potential therapeutic targets using Drosophila nephrocytes and human podocytes; Aim 2, Identify modifier genes for APOL1 renal toxicity using Drosophila genetic screening, and test them as potential therapeutic targets in nephrocytes and human podocytes; Aim 3, Use Drosophila as a drug screening platform to screen positive hits from a cell-based APOL1 drug screen. Accomplishing the above proposed aims will yield novel, ground-breaking discoveries to understand molecular mechanisms of APOL1 nephropathy. We will identify down-stream APOL1-RA target genes, identify potential therapeutic targets using Drosophila genetic screening plus human podocyte validation and screen the most effective and least toxic drug compounds that may eventually be used to treat APOL1 nephropathy.