# Using transcriptomics and ex vivo organotypic models to discover mechanisms of APOL1-associated podocytopathies

> **NIH NIH K01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $130,741

## Abstract

ABSTRACT
Chronic Kidney Disease (CKD) is common among African American (AA) patients. The excess risk for CKD in
this population is partially explained by genetic variations in the APOL1 gene (named G1 and G2) that are unique
to African ancestral populations. Understanding the molecular basis for the association between genetic variants
and the risk for kidney disease is an important goal in biomedical science. The APOL1 gene is unique to humans
and a few primates creating limitations to research approaches using conventionally available experimental
models. This career development research proposal is designed to train a promising early stage investigator to
address these issues by using organotypic kidney models derived from human inducible stem cells (iPSC) in
conjunction with state-of-the-art bioinformatics to interrogate human patient data and explore therapeutics. The
current proposal is designed to test the hypothesis that APOL1 kidney disease risk variants drive
transcriptional differences that can be identified by the integration of glomerular transcriptomes from
people with APOL1-associated kidney disease and ex vivo models, to gain insight into APOL1 function
in health and disease. Key preliminary data developed by the applicant demonstrates that a variant-dependent
APOL1 transcriptional signatures identified in human glomeruli are conserved in mouse models expressing
APOL1 variants. The applicant will acquire new skills in two general areas: 1) expertise in the use of novel ex
vivo culture models for mechanistic studies, and 2) computational and bioinformatics analysis of large datasets.
These skills will be acquired through mentorship, didactics and a pragmatic research program divided into three
specific aims: 1) Define APOL1 risk genotype-associated transcriptional phenotypes in podocytes derived from
isogenic cell lines homozygous for the G0, G1 and G2 alleles that are anchored to human glomerular gene
expression; 2) Anchor APOL1 variants-associated podocyte transcriptional phenotypes to NEPTUNE glomerular
gene co-expression modules and clinical outcomes, and identity compounds that could modulate such
phenotypes and associated subcellular processes, and 3) Test the chemical perturbagens’ ability to reverse the
APOL1 risk genotype transcriptional phenotype and identify kidney disease mechanisms. Completion of this
proposal will provide insights into APOL1 biology and function that could be translated to clinical technology by
providing early diagnosis and prognosis tools, identification of therapeutic targets and patient derived renal
models. Additionally this proposal aims to establish the Principal Investigator (PI) as an independent translational
scientist in nephrology. The plan includes mentored training in patient oriented research, extensive wet-lab
training in the production of organotypic models from iPSC lines as well as comprehensive coursework in
bioinformatics.

## Key facts

- **NIH application ID:** 10765669
- **Project number:** 5K01DK128304-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Agustin Gonzalez-Vicente
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $130,741
- **Award type:** 5
- **Project period:** 2023-01-18 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765669

## Citation

> US National Institutes of Health, RePORTER application 10765669, Using transcriptomics and ex vivo organotypic models to discover mechanisms of APOL1-associated podocytopathies (5K01DK128304-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10765669. Licensed CC0.

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