Project Summary:
Loss of vision is a significant medical, financial, and social burden on the people of Wisconsin. Glaucoma, the second leading cause of blindness worldwide, affects approximately 123,816 Wisconsinites or 2.1% of the total state population. In people over 75 years of age, this incidence more than doubles to 4.7%. Additionally, African American and Latino populations are at significantly higher risk for glaucoma development due to genetic and socio-economic factors. The progressive loss of sight due to glaucoma can be slow, with patients not realizing they have lost more than 40% of their visual field before seeing their doctor. Unfortunately, there are no current treatments to restore this lost vision and treatments to delay future losses can be expensive—$600-$2,500 annually. In fact, glaucoma is thought to cost Wisconsin more than $40,000,000 per year due to medical ($25,000,000), nursing home ($6,000,000), and support service ($9,000,000) costs according to the CDC Vision Health Surveillance System. And this cost is continuously rising with the aging population and economic inflation. The social burden of vision loss to patients, family, and caregivers is also significant due to loss of productivity and quality of life. Therefore, development of new treatments that restore vision and lessen these burdens would benefit both the state and citizens of Wisconsin.
Glaucoma, and other less common optic neuropathies, cause vision loss by disrupting the connection from the eye to the brain. Specifically, the axons projecting from the retinal ganglion cells (RGCs) through the optic nerve (ON) to multiple brain regions are damaged and RGCs themselves die secondarily over time. Current treatments can decrease the damage to axons, preserving some long-term vision. However, lost RGCs and synaptic reconnection of the remaining cells are never re-established. Developing new treatments or RGC cell replacement strategies requires a better understanding of the mechanisms of neurodegeneration and regeneration. Common mammalian models of glaucoma are similar to patients in that axon regeneration does not occur, and RGCs are susceptible to cell death. This makes understanding cell resilience and axon regeneration challenging. Fortunately, there are vertebrate models like the fish and frog that retain the ability to fully regenerate lost cells and connections in the central nervous system. This research team is using the zebrafish model organism to identify the basic biological mechanisms of successful ON regeneration with hopes of translating these mechanisms into new treatments for patients. Zebrafish respond to ON injuries with robust axon regeneration, near complete RGC survival, and restoration of vision. Genetically, zebrafish are about 70% similar to humans, and evolutionary conservation of several pro-regenerative mechanisms have been established, demonstrating the value of this model.
The goal of this pilot project is to determine if hypertranscription is occurring in RGCs during zebrafish ON regeneration and whether the mych, mycb, and top2b genes mediate hallmark mechanisms in this process. Proof of this mechanism will consolidate disparate observations in the field of nerve regeneration and define a new conceptual direction for future experiments and a R01 level grant application.