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

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.