# REGULATORS OF CALCINEURIN PATHWAYS AS DIAGNOSTIC AND THERAPEUTIC TARGETS FOR NEPHROTIC SYNDROME

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $658,609

## Abstract

Nephrotic syndrome and other glomerular diseases are major causes of chronic kidney diseases world-wide.
The molecular mechanisms of NS are not completely known, and this major gap in knowledge is an impediment
to treating patients with NS and developing new treatments. A more complete understanding of the mechanisms
underlying NS is critical for identification of robust non-invasive diagnostic tools and precise effective treatment
options. In preliminary data, we identified pathogenic variants in the genes regulator of calcineurin (CN) types 1-
3 (RCAN1-3) in patients with NS. We showed that cells expressing mutant RCAN1 displayed elevated CN activity
and increased apoptosis. These phenotypes were rescued by pharmacological inhibition of CN. Our findings
suggest that variants in RCAN genes are novel genetic causes of NS, and that modulators of CN signaling may
represent targeted therapy for individuals with NS induced by RCAN mutations, the more common idiopathic NS
and other glomerular diseases. Despite the fact, that unregulated CN activation is central to the pathogenesis of
multiple glomerular disease processes and CN inhibitors (CNIs) are often used for treatment, the signaling
pathways regulated by RCAN proteins specifically are not well understood. Further, only ~30-50% of patients
with steroid resistant NS will achieve remission with CNI treatment and there are currently no biomarkers to
predict therapy response despite major side effects of CNI including nephrotoxicity. The overarching hypothesis
of this study is that genetic defects in RCAN genes cause CNI responsive NS by reducing podocyte viability due
to aberrant cytoskeletal dynamics that can be ameliorated by targeting modulators of RCAN activity. We will test
our hypothesis through the following aims: 1) Determine the effect of pathogenic variants in RCAN genes on CNI
therapy response in patients with NS, 2) Determine the molecular mechanisms mediating the aberrant
phenotypes caused by pathogenic RCAN variants in patient derived iPSC podocytes and iPSC-kidney
organoids, and 3) Identify targeted therapies that can rescue the aberrant RCAN phenotypes in ex-vivo
podocytes. Data generated from these studies will define the role of genetic defects in RCAN genes in disease
pathogenesis and CNI therapy response in patients with NS. In addition, the study will reveal podocyte signaling
mechanisms that are dysregulated due to defective RCAN genes and ultimately lead to identification of novel or
repurposed therapeutic alternatives to CNI treatment.

## Key facts

- **NIH application ID:** 10771970
- **Project number:** 5R01DK134347-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Rasheed Adebayo Gbadegesin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $658,609
- **Award type:** 5
- **Project period:** 2023-02-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10771970

## Citation

> US National Institutes of Health, RePORTER application 10771970, REGULATORS OF CALCINEURIN PATHWAYS AS DIAGNOSTIC AND THERAPEUTIC TARGETS FOR NEPHROTIC SYNDROME (5R01DK134347-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10771970. Licensed CC0.

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