A New Model of Human Primary Open-Angle Glaucoma

DESCRIPTION (provided by applicant): Elevated intraocular pressure (IOP) is a causative risk factor for the development and progression of glaucoma. Several new pathogenic pathways have been identified that cause primary open-angle glaucoma. Glaucomatous mutations in Myocilin (MYOC) damage the trabecular meshwork and elevate IOP in humans and in mice. Aqueous humor levels of the pro-fibrotic cytokine TGF[unreadable]2 are elevated in POAG patients, and TGF[unreadable]2 elevates IOP in perfusion cultured anterior segments and in rodent eyes. Animal models of glaucoma are important to discover and better understand molecular pathogenic pathways and test new glaucoma therapeutics. Although a number of different animal models of glaucoma have been developed and characterized, there are no true models of human POAG. Our overall hypothesis is that using human POAG relevant transgene (i.e. mutant MYOC and TGF[unreadable]2) expression in mouse eyes to elevate IOP will cause glaucomatous optic neuropathy and retinopathy in mice. The following two specific aims will address and test this hypothesis: (SA#1) We will conduct a limited mouse strain survey to identify a mouse strain(s) with MYOC- or TGF[unreadable]2-induced ocular hypertension that develops glaucomatous optic neuropathy and retinopathy. (SA#2) Once we have identified a sensitive strain, we will further characterize glaucomatous damage in this strain by assessing optic nerve and RGC damage and testing visual functions over time (0-12 weeks). The development of a relevant mouse model of human POAG will allow the molecular dissection of pathogenic pathways using the power of mouse genetics as well as provide an important new model for assessing new therapeutic approaches for the treatment of glaucoma. PUBLIC HEALTH RELEVANCE: Glaucoma is a leading cause of irreversible visual impairment and blindness in the United States. Elevated eye pressure damages tissues in the back of the eye. This study will develop a new mouse model of human glaucoma, which will allow a better understanding of the disease process and provide an appropriate model to test new glaucoma therapies.