# Molecular Pathobiology of Alport Syndrome

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $508,070

## Abstract

Hundreds of variants in the COL4A3, COL4A4 and COL4A5 genes cause a broad range of
glomerulopathies affecting the function of the glomerular basement membrane (GBM) in patients
with Alport syndrome. These genes encode the assembly of collagen IV α345 scaffolds, the major
constituent of the GBM. The pathogenic variants lead to a broad array of clinical manifestations,
ranging from microscopic hematuria to end stage renal disease. The underlying mechanisms
linking these variants with GBM abnormalities and renal failure remain obscure. Current therapy
is limited to treatment with ACE inhibitors to slow progression and new therapies are in urgent
need.
How genetic variants of the α345 scaffold cause Alport syndrome remains unknown. Here, we
focus on Z-variant causing Alport syndrome without loss of the α345 scaffold but rather reduction-
or loss-of-function effect (hypomorph variant). We use this variant as a vanguard to decipher the
pathogenic mechanism of the α345 collagen IV in Alport GBM and develop new forms of therapy.
In Aim 1, we will utilize a new Z-variant animal model to understand mechanisms of α345 collagen
IV dysfunction. In Aim 2, we will determine exact defects caused by Z-variant and similar
pathogenic variants at protein and cellular levels to identify specific targets for small molecule
therapies. In Aim 3, we will test protein replacement therapy and screen for pharmacological
chaperones correcting assembly and stability of the collagen IV α345 scaffold.
The completion of the Aims will advance our knowledge about Alport pathogenesis and lay out
foundation for therapy development addressing causative mechanisms in Alport syndrome.

## Key facts

- **NIH application ID:** 10835097
- **Project number:** 5R01DK131101-03
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Sergey Petrovich Budko
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $508,070
- **Award type:** 5
- **Project period:** 2022-09-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10835097

## Citation

> US National Institutes of Health, RePORTER application 10835097, Molecular Pathobiology of Alport Syndrome (5R01DK131101-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10835097. Licensed CC0.

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