# Mechanisms involved in podocyte damage in Alport Syndrome

> **NIH NIH R01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2024 · $613,580

## Abstract

During the progression of most chronic kidney diseases (CKD) podocytes are lost, and injury to glomerular
endothelial cells, and changes in the composition of the glomerular basement membrane (GBM) lead to
alterations of the structure and function of the glomerular filtration barrier. Understanding the mechanisms
that induce glomerular cell damage could possibly pave the way to the discovery of new pathways that
can be targeted to slow kidney disease progression or possibly reverse it.
Data presented in this proposal, using the glomerulus on a chip platform and the FUCCI mouse model that allows
tracking of the cell cycle changes in vivo, show that podocytes present an altered binding to their GBM, they exit
their quiescent state, and are lost during disease progression in Alport Syndrome (AS) mice, our model of CKD
characterized by a defective GBM. We have evidence that miR-193a is upregulated specifically in mouse and
human AS podocytes and that its inhibition favors podocyte survival and modulate podocyte interactions with
their GBM. Based on our data, we hypothesize that re-establishing glomerular function by modulating
important molecular pathways that are responsible for podocyte survival prevents further injury, thus
slowing kidney disease progression.
Using multiple transgenic AS FUCCI mice and in vitro human systems, we will study the molecular mechanisms
that regulate the podocyte cell cycle and their interaction with a defective GBM, typical of AS. Specifically, in Aim
1 we will study in vitro how modulation of miR-193a can “re-program” cellular signaling networks that influence
podocyte biology. In Aim 2 we will perform in vivo studies to determine the therapeutic effect of miR-193a inhibitor
delivered as cargo of an innovative delivery vehicle based on peptide amphiphile micelle nanoparticles
specifically designed to target podocytes in our AS colonies. Successful completion of this proposal will provide
novel insights into key factors critical for maintenance of glomerular structure and function. Importantly, this
knowledge would likely be applicable to other forms of CKD and possibly facilitate the discovery of new
therapeutic agents tailored specifically to sustain podocyte survival and minimize glomerular damage.

## Key facts

- **NIH application ID:** 10839879
- **Project number:** 5R01DK133459-03
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** Stefano Da Sacco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $613,580
- **Award type:** 5
- **Project period:** 2022-08-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839879

## Citation

> US National Institutes of Health, RePORTER application 10839879, Mechanisms involved in podocyte damage in Alport Syndrome (5R01DK133459-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10839879. Licensed CC0.

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