Grant: CIHR Fellowship

Glaucoma, characterized by the death of retinal ganglion cells (RGCs), is the leading cause of irreversible blindness worldwide. Glaucoma shares pathological features with a number of neurodegenerative conditions, most notably with Alzheimer's disease. One of the main features of Alzheimer's disease is neurofibrillary tangles of aggregated tau, a microtubule stabilizing protein. Our recent data suggest that the microtubule stabilizing protein tau accumulates in RGCs soon after the onset of glaucoma. Tau has been shown to inhibit calcium efflux making neurons vulnerable to stress-induced cell death. However, a clear molecular link between calcium dysregulation pathways and early RGC dysfunction and damage in glaucoma has been lacking. In addition, our current understanding of calcium dynamics in RGCs and how they are altered in glaucoma is poorly understood due to lack of reliable calcium imaging techniques in living RGC. To address this knowledge gap, we will optimize a novel two-photon laser scanning microscopy to characterize intracellular calcium dynamics in living RGCs in early stage glaucoma. Additionally, using this powerful technique, we will investigate the molecular mechanisms leading to loss of calcium homeostasis in RGCs. Furthermore, we will address the fundamental question of whether calcium pathway modulation serves as a therapeutic target for vulnerable RGCs in glaucoma. The outcome of this project will provide important insights into the role of pathways that regulate calcium influx and efflux in RGCs and their effect on structural and functional neuronal damage in glaucoma. Importantly, this study will identify strategies to regulate calcium homeostasis in RGCs and might validate new therapeutic approaches to counter neurodegeneration and loss of visual function in glaucoma.