New Glaucoma Models Mined from an Inbred Genetic Reference Panel
Millions of people are affected by glaucoma and some lose their vision due to this disease. To develop new drugs to treat glaucoma or to understand why glaucoma causes vision loss, it is important to have accurate models of the disease. Unfortunately, there are not enough models available that truly reflect the human disease. We hope to change that. In our study, we will identify and characterize new glaucoma models that share the disease phenotypes of humans. These models will be a very useful resource for all vision scientists.
Glaucoma is the second leading cause of blindness in the world. Our chances of losing vision to this disease markedly increase as we age and if we have relatives that have glaucoma. Despite its prevalence, we don’t fully understand what causes glaucoma, why some people lose their vision faster than others, and how we can stop the progression of vision loss. In our BrightFocus-funded study, we will identify and characterize strains of mice within the BXD genetic reference panel that mimic primary open angle glaucoma (POAG), primary angle closure glaucoma (PACG), normal tension glaucoma (NTG) and ocular hypertension. Our overall goal is to meet the urgent need for new, rigorously characterized and reproducible mouse glaucoma models that appropriately reflect the variety of glaucoma subtypes recognized in the human population. Any glaucoma model that we identify is spontaneous and is due to the particular set of polymorphisms in the genome of each individual strain, similar to the human condition. Moreover, the phenotype of each strain is highly reproducible and the supply of mice from each strain is unlimited. These models can be used by multiple investigators to identify disease mechanisms and/or evaluate new glaucoma therapies.
About the Researcher
For over 15 years, my laboratory has been identifying the genetic cause of aberrant ocular endophenotypes. From 2000-2005, my laboratory served as the Eye Domain of the Tennessee Mouse Genome Consortium (TMGC) in which various laboratories across the state of Tennessee used a forward genetics ENU-based mutagenesis screen to produce recessive mutations that affect the eye and brain. Using high throughput clinical and laboratory protocols, we identified seven mutant lines of mice with ocular abnormalities. In one of the lines of mice, we also identified a mutation in retinoschisin (Rs1h), making this the first murine model of X-linked retinoschisis in which the gene is expressed. Continuing with this line of investigation, we expanded our approach to include systems genetics methodologies and the BXD genetic reference panel of mice to identify modulators of glaucoma-related endophenotypes such as elevated intraocular pressure (IOP) and optic nerve (ON) damage. We are also mining the BXD family of mice to identify new spontaneous and polygenetic preclinical models of glaucoma. Although there are several meritorious glaucoma models that are currently available in species ranging from mouse to turkey to monkey, no model system completely mimics the array of human disease presentation. Therefore additional models of glaucoma are still an unmet need of the vision research community. It is my hope that the use of polygenetic spontaneous mouse models of glaucoma will lead to faster development of translational treatments for this highly prevalent blinding disorder.
I am extremely honored and grateful to have been selected as a recipient of a BrightFocus Glaucoma award. The support of the Foundation and its donors is instrumental in providing my laboratory the opportunity to work toward the identification of new models of glaucoma. It is often the farsightedness of foundations such as BrightFocus, that supports nascent yet innovative, ideas that may not attract federal support. I am confident that the preclinical glaucoma models that we identify and characterize will provide a huge value to the scientific community.
First published on: January 10, 2019
Last modified on: April 24, 2020