# Laminins And Glomerular Filtration

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $505,945

## Abstract

Project Summary
The glomerular basement membrane (GBM) is a major component of the glomerular filtration barrier. Of the
nine major GBM proteins, mutations in at least 4 of them cause human disease. Pierson syndrome (congenital
nephrotic syndrome with ocular and nervous system abnormalities) is caused by laminin beta2 (LAMB2) null
mutations; in contrast, LAMB2 missense mutations cause congenital nephrotic syndrome with less severe and
highly variable extrarenal manifestations. On the other hand, Alport syndrome is caused by mutations affecting
any one of three collagen IV genes (COL4A3, A4, and A5). These diseases have very different presentations
and rates of progression to ESRD, but the fact that a GBM defect is the initiating insult in both demonstrates
the importance of investigating GBM structure and function in order to better understand how to treat patients.
For over 20 years we have been interested in understanding the makeup of the glomerular filtration barrier and
how it becomes damaged and leaky to plasma proteins using our mouse models of Pierson and Alport
syndromes. Having determined why certain missense LAMB2 mutations cause nephrotic syndrome, here we
now propose to test protein therapy approaches designed to remedy defects in the GBM using both transgenic
and intravenous protein therapy modalities. Our preliminary data show that full-sized laminin trimers injected
i.v. reach the GBM, become stably integrated into the GBM, and moderately improve the filtration barrier in
Lamb2 null mice. This proof of concept suggests that improving GBM structure via the bloodstream is a viable
therapeutic option. We will use rationally designed chimeric matrix proteins that are much smaller than full-
sized laminin trimers to attempt to improve laminin polymerization in the GBM of novel mutant mice with
laminin polymerization defects, in the context of both nephrotic syndrome and Alport syndrome. In addition,
state of the art gene expression profiling of single cells will be used to determine how proper laminin
polymerization impacts podocyte homeostasis, as well as that of other glomerular cells. The results of these
studies will provide important new insights into laminin and basement membrane biology and lead to potential
therapies for human glomerular disease involving GBM defects.

## Key facts

- **NIH application ID:** 9944486
- **Project number:** 5R01DK078314-12
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** JEFFREY H MINER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $505,945
- **Award type:** 5
- **Project period:** 2008-03-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944486

## Citation

> US National Institutes of Health, RePORTER application 9944486, Laminins And Glomerular Filtration (5R01DK078314-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9944486. Licensed CC0.

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