Characterization of a Zebrafish Model of Wet Macular Degeneration

The purpose of this study is to develop a new model of wet macular degeneration using zebrafish, a common pet store fish. The advantages of zebrafish are that they are small, inexpensive, have retinas very similar to humans, and can be used for large-scale drug screens.  We have characterized a particular zebrafish strain which has growth of abnormal vessels in the retina, very similar to what happens in wet AMD. We will perform drug screens in this zebrafish to identify drugs that inhibit abnormal blood vessel growth and may show promise as therapeutics for macular degeneration.

The first part of our grant looks at the movement and behavior of macrophages, immune cells in the retina, which are thought to be important in the pathogenesis of macular degeneration. We will do live imaging of macrophages during normal development as well as in a particular zebrafish mutant which has aberrant growth of vessels in the eye, mimicking macular degeneration. We will then use genetic tools to get rid of macrophages to see how this affects vessel growth. The second part of our grant is to investigate the role of a candidate protein that may be involved in mediating blood vessel growth in the zebrafish eye. This protein is expressed specifically in newly formed vessels in the retina. We will look at the function of this protein in vessel growth in the zebrafish eye by examining zebrafish that are lacking this protein, as well as using an FDA-approved drug that inhibits the activity of this protein on the vessels.

The third part of our experiment is to conduct a pilot drug screen of molecules to see whether they can inhibit aberrant vessel growth in our zebrafish mutant which mimics macular degeneration. We will put zebrafish embryos in 96 well plates and then add individual drugs to each well, and then determine whether the drug can inhibit the growth of abnormal blood vessels in the zebrafish eye. Using a library of FDA-approved drugs, we hope to find drugs that may be effective in inhibiting vessel growth and thus may be effective as new therapeutics for macular degeneration.

This proposal is innovative in that it uses a novel organism to model macular degeneration. Most models of AMD involve rodents, which are expensive and therefore not as useful for high throughput drug approaches. The advantages of zebrafish are that they are small, inexpensive, have retinas very similar to humans, and can be used for large-scale drug screens. After the completion of this proposal, I hope to demonstrate the utility of zebrafish as a model for macular degeneration.  I plan to utilize this novel model of macular degeneration to identify new proteins that may be involved in abnormal vessel growth in the retina.  I hope the insights we find will lead to new cures for macular degeneration.