Multimodal Characterization of a Novel Inherited Mouse Model of Glaucoma - ABSTRACT Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide, affecting over 80 million people. It is characterized by the progressive loss of retinal ganglion cells (RGCs) and optic nerve damage. Elevated intraocular pressure (IOP) is causal risk factor of glaucoma. While current treatments focus on lowering IOP, there is a critical need for therapeutic strategies that target neuroprotection, as no existing treatments effectively prevent or slow RGC death and axonal degeneration. Current animal models for glaucoma, such as inducible IOP elevation models have limitations in replicating the gradual, spontaneous progression of human glaucoma. Moreover, inherited mouse models, such as DBA/2J, exhibit slow and variable disease progression and anterior segment inflammation. Glis1 knockout (KO) mice offer a novel genetic model to studying glaucoma. GLIS1 is a Krüppel-like transcription factor predominantly expressed in the trabecular meshwork (TM) and undetected in the retina. Importantly, GLIS1 deficiency induces progressive degeneration of TM, leading to IOP elevation. Thus, this model provides a unique system to study ocular hypertension-induced glaucomatous neurodegeneration without confounding effects of Glis1 deficiency in the retina. Moreover, Glis1 KO mice exhibit no major abnormalities outside the drainage angle specific phenotype, making them ideal for longitudinal studies. Aim 1 will characterize glaucoma-relevant phenotypes in Glis1 KO mice across two genetic backgrounds (C57BL/6J and 129S6/SvEvTac), evaluating structural and functional changes, including axonal degeneration, RGC loss, dendritic changes, and neuroinflammatory responses. Aim 2 will identify molecular pathways associated with glaucomatous neurodegeneration using single cell RNA sequencing (scRNA-seq) of RGCs. Integrating findings of the gene expression changes with human POAG genome-wide association studies (GWAS) with help prioritize candidate genes contributing to glaucoma. Our study will establish the Glis1 KO model as a valuable resource for the glaucoma research community, addressing limitations of existing models by offering a more physiologically relevant and reproducible model for investigating glaucoma pathogenesis. Insights from this experimental glaucoma model may lead to novel strategies for glaucoma treatment.
