Mechanisms of Hypertranscription Mediated Nerve Regeneration in Fish and Mammals

Project Summary:

Vision loss and blindness caused by optic neuropathies, as exemplified by glaucoma, are a significant financial and social burden on the population of Wisconsin. No treatments are currently available to recover lost vision after the onset of these diseases. The cause of the vision loss is a disconnection from the eye to the brain that triggers the death of specific cells in the eye. Mammalian models of this disease show similar degeneration and cell death. Surprisingly, fish and frog models can survive this injury and actively regenerate lost connections. This project aims to identify the basic biological mechanisms of this recovery in the zebrafish model and test if they can be applied to mouse models of the disease. Specifically, the project team proposes that hypertranscription, a state of broadly elevated gene expression, is a key mechanism of neuroprotection and nerve regeneration. Based upon preliminary data from the team's laboratory, they will test the effect of knocking down two different “universal amplifying” factors in zebrafish and activating them in mice. They will then compare the transcriptome-wide effect of these manipulations in both species to identity how recovery occurs in fish and fails in mammals. The results will suggest evolutionary differences that dictate the capacity for neuroprotection and nerve regeneration. These results will contribute to a basic understanding of nerve injury and regeneration and point towards therapeutic targets for future development. This project also positions the research team with the tools and preliminary data to expand this line of inquiry. Their hope is that the result generated here will be applied toward the development of future treatments for blinding diseases.