Direct Observation and Manipulation of Energy Regulation in RGCs During Glaucoma
Glaucoma is caused by damage and death of retinal ganglion cells that connect the eye to the brain. While many retinal ganglion cells die during the course of glaucoma, some persist despite the harsh disease environment. We will determine how these retinal ganglion cells survive by directly observing their energetic characteristics over the course of a disease model in mice. This information will be used to reprogram the energetic state of retinal ganglion cells to attempt their rescue in conditions of glaucoma.
Glaucoma causes vision loss by damaging and killing retinal ganglion cells (RGCs), the only relay of visual information between our eye and brain. Although, many RGCs die during the course of vision loss due to glaucoma, there is a sizable population that survives despite the disease. A main focus of my research is understanding what makes surviving RGCs resilient so as to transfer these characteristics to RGCs that might otherwise die. Much like ourselves, RGCs rely on a constant intake of fuel to provide energy for normal function and survival. Neurodegenerative conditions like glaucoma can alter how metabolites are supplied to RGCs, and the way they are broken down to produce energy. We believe that knowing how surviving RGCs maintain their energy requirements, in contrast to RGCs that die, will allow us to formulate new therapeutic strategies to treat glaucoma. We are using a mouse model of glaucoma paired with live single RGC imaging of proteins called biosensors that can read out the activity of different molecular pathways during the course of disease (for example glycolysis or oxidative phosphorylation). We are using biosensors for multiple aspects of energy supply and production in RGCs and will correlate their activity with RGC survival or death. This powerful combination of techniques will allow for us to create a complete picture of how surviving RGCs cope with glaucoma, and at the same time show pitfalls that may explain why some die. Our overall goal is to develop new strategies of RGC preservation. We will use the data generated in our imaging experiments to design gene therapy approaches. In these experiments we will either boost or repress gene expression of pathways specific to surviving RGCs or dying RGCs, respectively. We hope that approaches that benefit mouse models of glaucoma will be translatable to human patients.