# Comparative Multi-Omics Analysis of the Iridocorneal Angle Identifies an Immune–Fibrotic Profile in the DBA/2J Glaucoma Mouse Model

## TL;DR

This study combines gene and protein data from a mouse model of glaucoma to uncover immune and fibrotic changes linked to the disease.

## Contribution

The first integrated transcriptomic and proteomic profiling of the iridocorneal region in a spontaneous glaucoma mouse model.

## Key findings

- Upregulated genes in DBA/2J mice are enriched in extracellular matrix remodeling, TGF-β signaling, and inflammation.
- Proteomic data confirm increased complement components and autophagy markers, indicating immune–fibrotic interactions.
- Cross-referencing with human data reveals overlap with glaucoma-associated genes like LTBP2, LOXL1, and COL11A1.

## Abstract

We present the first integrated transcriptomic and proteomic profiling of the iridocorneal region in the spontaneous murine glaucoma model DBA/2J and DBA/2J-Gpnmb+/Sj controls to define molecular changes associated with ocular hypertension and glaucoma. Using RNA sequencing and label-free quantitative proteomics, we identified over 20,000 transcripts and 8500 proteins, creating a comprehensive molecular atlas of glaucoma-related alterations in DBA/2J mice. Principal component and differential expression analyses revealed distinct genotype-specific molecular signatures. In DBA/2J mice, upregulated genes were enriched in pathways related to extracellular matrix remodeling, collagen organization, TGF-β signaling, and inflammation. Proteomic data confirmed increased levels of complement components, antigen presentation proteins, and autophagy markers. Integrated analyses identified 29 genes upregulated at both transcript and protein levels, primarily involved in extracellular matrix structure and immune regulation. Downregulated genes were associated with melanocyte differentiation and pigment-organelle function, including Pmel, a gene implicated in pigmentary glaucoma. Cross-referencing with human genome-wide association studies data revealed overlap with glaucoma-associated genes (LTBP2, LOXL1, COL11A1, VCAM1), alongside reduced expression of Angpt and Lmx1b, linked to ocular hypertension. Together, these findings support the existence of an immune-fibrotic feed-forward loop and implicate collagen–elastic fiber dysfunction as a central mechanism in glaucoma pathogenesis.

•Integrated transcriptomic–proteomic atlas of the DBA/2J iridocorneal region.•ECM, TGF-β, and cytokine pathways define a pro-fibrotic anterior segment state.•Complement and autophagy networks reveal immune–fibrotic cross talk.•LOXL1, LTBP2, ANGPT2, and LMX1B misregulated in glaucomatous angle tissue.•GPNMB loss links ECM remodeling with innate immune activation in glaucoma.

Integrated transcriptomic–proteomic atlas of the DBA/2J iridocorneal region.

ECM, TGF-β, and cytokine pathways define a pro-fibrotic anterior segment state.

Complement and autophagy networks reveal immune–fibrotic cross talk.

LOXL1, LTBP2, ANGPT2, and LMX1B misregulated in glaucomatous angle tissue.

GPNMB loss links ECM remodeling with innate immune activation in glaucoma.

This study presents the first integrated transcriptomic and proteomic atlas of the iridocorneal region in DBA/2J mice, revealing coordinated activation of extracellular matrix remodeling, TGF-β, and immune pathways linked to glaucoma progression. The concordance between RNA and protein data identifies conserved risk genes and highlights an immune-fibrotic network underlying angle remodeling, providing new molecular insights into the pathogenesis of ocular hypertension and pigmentary glaucoma.