Defining the role of RIG-I in glaucoma pathogenesis and response to viral infection

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

ABSTRACT: Immune mechanisms have been identified as increasingly important features in the pathogenesis of glaucoma and ocular hypertension. Rare immunogenetic syndromes, including Singleton-Merten syndrome (SGMRT), provide a window into the role of the innate immune system in glaucoma. We recently identified 3 multigenerational pedigrees with isolated juvenile glaucoma or SGMRT. These families all carry missense variants at the same amino acid residue of the DExD/H-box RNA helicases RIG-I, but have varying phenotypic spectrum. We found that these variants activate RIG-I and downstream Type I interferon signaling in the absence of exogenous RNA ligands, and a mouse model of one of these variants recapitulates features of SGMRT including elevated IOP and glaucomatous retinal ganglion cell loss. In this proposal, we seek to extend our findings by (i) defining the molecular mechanism by which RIGI variants cause glaucoma in our mouse model using genetic perturbation, histologic, and single cell transcriptomics analyses; (ii) defining the triggers that exacerbate SGMRT and may explain the phenotypic variability of this condition, including viral infections such as Zika virus; (iii) testing therapeutic interventions to rescue the sequela of RIG-I activation and glaucoma in patient cells and our mouse model. Our underlying hypothesis is that RIG-I activation in fibroblasts, macrophages, and endothelial cells in the trabecular meshwork and Schlemm’s canal lead to Type I interferon signaling, increased in intraocular pressure, and glaucoma. We additionally hypothesize that these pathways can be exacerbated by Zika infection or dsRNA triggers and rescued by Type I interferon blockade. Our overarching goal is to define the immune mechanisms that drive glaucoma. This proposal will inform our understanding of the contribution of the immune system to SGMRT as well as more common forms of glaucoma that may be driven by RIG-I activation.