Forward Genetic Analysis of Glaucoma-Related Phenotypes in Zebrafish

Project Description Narrative:

The glaucomas are a group of vision impairing diseases characterized by retinal ganglion cell death, and frequently associated with elevated intraocular pressure. Glaucoma is the second leading cause of blindness worldwide, with a prevalence of approximately 1.0% overall. However, specific groups including aged individuals, African Americans, and those with myopia are at greater risk. For example, for individuals over 40, the incidence of glaucoma is 1.9%. The incidence increases further to 3.5% in people over 70. The complex nature and limits of traditional genetic approaches in humans and mammalian model systems has prevented the identification of most genes that impact glaucoma.

Over the past few, the research team on this project has developed methodologies and tools in zebrafish to detect and measure glaucoma-associated phenotypes in both embryonic and adult zebrafish. Zebrafish show similar ocular anatomy and physiology to humans and are highly amenable to largescale forward genetic screens to identify genes and signaling pathways that affect normal homeostasis or cause disease.

In the current study, the researchers will pursue a genetic screen in zebrafish to identify mutants that display anterior segment dysgenesis, elevated intraocular pressure, and/or retinal ganglion cell degeneration. They will then use these mutants to identify the causative loci for each mutation. Finally, they will investigate whether any of the genes or pathway interactants identified from these efforts are affected in orthologous loci from human glaucoma patients.