# Molecular Pathobiology of Alport Syndrome

> **NIH NIH R56** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $99,999

## 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
function of the α345 collagen IV in GBM and develop new therapeutic approaches against Alport
syndrome. In Aim 1, we will utilize new Z-variant animal models to understand mechanisms of
α345 collagen IV function and dysfunction. In Aim 2, we will determine exact functional 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 identify candidates for potential
therapy by performing in vitro screening of natural and synthetic small molecules affecting
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 development of therapy against Alport syndrome.

## Key facts

- **NIH application ID:** 10476071
- **Project number:** 1R56DK131101-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Sergey Petrovich Budko
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $99,999
- **Award type:** 1
- **Project period:** 2021-09-23 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476071

## Citation

> US National Institutes of Health, RePORTER application 10476071, Molecular Pathobiology of Alport Syndrome (1R56DK131101-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10476071. Licensed CC0.

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