UCSF

Macular degenerations impact millions across the globe, with this number predicted to grow due to lack of effective therapies to combat the disease. The complex etiology of macular degenerations makes their developing treatments difficult. This thesis seeks to explore the underlying mechanisms and how they contribute to the disease in three ways. First, I show how ceramide accumulation drives the release of extracellular vesicles from the retinal pigment epithelium. These extracellular vesicles contain pro-inflammatory cargo and are predominantly released from the apical surface of the retinal pigment epithelium, towards the retina. This disrupts communication in the retina and recruits harmful microglia into the subretinal space. Second, I show that the retinal pigment epithelium are uniquely mechanosensitive to their environment, such that “drusen-in-a-dish” models, where I use biologically inert silica beads, can drive mitochondrial fragmentation in retinal pigment epithelium and disrupt retinal pigment epithelium homeostasis. These can be extrapolated towards mechanisms of disease in age-related macular degeneration. Finally, I show that an Food and Drug Administration-approved drug for osteoporosis and Paget disease, zoledronic acid, can be repurposed to reduce ceramide levels within the retinal pigment epithelium. And by reducing ceramide levels, many of the disruptions to retinal pigment epithelium function can be ameliorated and improve vision in mouse models of inherited macular degenerations. Together, these findings can be used for a better understanding of macular degenerations and hopefully pave the way for a curative intervention.