# Integrating Drosophila and human podocyte studies to discover APOL1 renal toxicity mechanism and therapeutic targets

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $347,625

## Abstract

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.

## Key facts

- **NIH application ID:** 9876992
- **Project number:** 7R01DK120908-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** ZHE HAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,625
- **Award type:** 7
- **Project period:** 2019-03-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9876992

## Citation

> US National Institutes of Health, RePORTER application 9876992, Integrating Drosophila and human podocyte studies to discover APOL1 renal toxicity mechanism and therapeutic targets (7R01DK120908-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9876992. Licensed CC0.

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