# Studies on the structure of basement membranes

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $758,503

## Abstract

The collagen IVα345 (Col-IVα345) scaffold, the major constituent of the glomerular basement membrane (GBM),
is a critical component of the kidney glomerular filtration barrier. In chronic kidney disease, affecting hundreds
of millions of people worldwide, over two thousand genetic variants occur in the COL4A3, COL4A4, and
COL4A5 genes that encode the α3, α4, and α5 chains of the Col-IVα345 scaffold. The chains are the
autoantigens in Goodpasture’s (GP) autoimmune disease, mutated in Alport syndrome, and dysfunctional in
diabetic nephropathy (DN). The rationale development of therapy hinges on gaining new understandings of
pathogenic mechanisms. GP disease, a renal pulmonary disorder, continues to serve as the vanguard for
unlocking these medical mysteries. Among our discoveries are: a) the crystal structure of the NC1 hexamer
of the α345 collagen IV scaffold, b) discovery of the primordial chloride pressure and its constraint against
neoepitope formation in Goodpasture’s disease3, c) discovery of functionality of the α345 NC1 hexamer in
the assembly of the GBM as an ultrafilter of proteins, d) development of the collagen triple-helix mapping
tool, e) capacity of NC1 domain to home in the assembly of basement membranes, and f) detrimental effect
of high glucose on the BM modifying enzymes. These published discoveries, together with substantial
amount of unpublished pilot data, provide the framework for four specific aims. Our overarching hypothesis is:
Col-IVα345 tethers macromolecules forming supramolecular complexes, perturbation of which, in genetic and
acquired disorders, cause glomerulopathies. The achievement of the aims will yield new insights into the
etiology of GP, the structure and assembly of collagen IV scaffolds and binding partners, and the molecular
mechanisms of underlying DN. This knowledge is of fundamental importance for the rationale design of
therapies that target the primary cause disease.

## Key facts

- **NIH application ID:** 10981504
- **Project number:** 2R01DK018381-53
- **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:** $758,503
- **Award type:** 2
- **Project period:** 1986-09-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981504

## Citation

> US National Institutes of Health, RePORTER application 10981504, Studies on the structure of basement membranes (2R01DK018381-53). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10981504. Licensed CC0.

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