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Oxidative stress is a common feature of most retinal and neurodegenerative disease and a major factor leading to retinal and neural cell death. My laboratory studies the OXR1 family of oxidative stress resistance genes and their roles in preventing neurodegenerative diseases. Our projects are to test OXR1 gene therapy and its ability to prevent or delay retinal degeneration and preserve vision. We are also exploring the molecular mechanisms responsible OXR1 mediated neuroprotection.

In collaboration with the laboratory of Hemant Khanna (UMass Medical School Dept. of Ophthalmology and Visual Sciences and the Horae Gene Therapy Center) we are testing the ability of OXR1 to delay loss of visual function in mouse models of several retinal degenerative diseases.

Depletion or loss of OXR1 causes cells to become very sensitive to oxidative stress and its over expression results in levels of resistance that are much greater than normal cells. OXR1 depletion has been observed in several mouse models of retinal degenerative diseases. Thus, we expect that restoring high level OXR1 expression will protect the retinal neurons from oxidative stress induced death. We have also found that increasing OXR1 expression in cells that have normal levels of OXR1 greatly enhances their resistance to oxidative stress. Therefore, we predict that high-level expression of OXR1 will increase oxidative stress resistance and retinal degeneration in retinal diseases in which OXR1 is expressed at normal levels.

We have tested this hypothesis in the rd1mouse model of retinal degeneration. We have shown a retention of visual function in eyes treated with a gene therapy vector that overexpresses OXR1 at a time when the contralateral eyes of the rd1mice have lost all visual function. The rd1 mouse model is a particularly aggressive and rapid onset of blindness model. We are now testing other mouse models such as the rhodopsin mutant mouse, which is a model for the most common form of retinitis pigmentosa in humans. This mouse has a much less aggressive and later onset of cone cell death than the rd1mouse model. This suggests that oxidative stress is much less severe than in the rd1 mutant mouse and therefore more amenable to the reduction in oxidative stress that results from OXR1 mediated gene therapy.

We are also determining the molecular basis of OXR1 mediated neuroprotection in order to better understand how this gene functions. It is known that OXR1 is critical for the prevention of oxidative stress induced neurodegeneration. It has also been shown to function as a regulatory element that controls the expression of a number of transcriptional regulatory elements that control the cells’ responses to oxidative stress, apoptosis, the cell cycle, and DNA repair. We are determining the gene expression pattern changes that occur when OXR1 is overexpressed and what the roles of specific isoforms are and how they differ from one another in the responses they generate and the level of oxidative stress resistance they confer.


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