Retinal Ganglion Cell Dendrite and Synapse Regeneration in Glaucoma: the Role of Insulin Signaling.

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Glaucoma is the leading cause of irreversible blindness worldwide. Loss of vision in glaucoma is caused by the selective death of retinal ganglion cells (RGCs). Rapid retraction of RGC dendrites with synapse disintegration, identified as an early pathological change after glaucomatous injury, leads to neuronal dysfunction and death. Many studies have focused on axonal regeneration, yet little is known about the ability of RGCs to regenerate dendrites. We recently demonstrated that insulin administered after substantial dendritic arbor shrinkage promoted robust RGC dendrite regeneration after optic nerve axotomy and in a mouse glaucoma model. However, several key questions remain unanswered: 1) does insulin regenerate synapses and restore neuronal function after glaucomatous damage? 2) Is impaired insulin signaling a trigger for dendritic pathology in glaucoma? 3) What are the mechanisms driving insulin-mediated dendrite regeneration? 4) What is the translational potential of insulin for RGC repair? In this application, we propose studies that will fill this knowledge gap and test the overarching hypothesis that insulin signaling is crucial for dendrite regeneration and functional restoration in glaucoma. We will use established models of glaucoma in mice and non-human primates as well as gain- and loss-of-function paradigms and innovative approaches in three independent, yet complementary, specific aims. In Aim 1, we will test the hypothesis that insulin regenerates dendrites and synapses leading to sustained restoration of neuronal function. These studies will also determine whether different RGC subtypes have the ability to mount a strong regenerative response and reestablish appropriate synaptic connectivity. Experiments outlined in Aim 2, will test the hypotheses that: i) impaired insulin signaling impinging on the mammalian target of rapamycin (mTOR) mediates early dendritic pathology and synapse elimination, and ii) insulin-mediated dendrite regeneration involves downstream bona fide effectors of protein translation and cytoskeletal regulation. In Aim 3, we will test the hypothesis that insulin treatment, including gene therapy, will effectively promote long-term RGC dendrite regeneration and restore visual function in non- human primate glaucoma. We will capitalize on our ability to use longitudinal in vivo imaging and electrophysiological techniques to monitor disease onset, progression, and recovery. The outcome of this application will have a major impact on our understanding of novel mechanisms and targets that promote RGC dendritic and synaptic regeneration as well as restoration of visual function. Importantly, this project will generate rigorous and compelling pre-clinical data that will serve as a knowledge-translation springboard towards the clinical development of insulin as a therapeutic strategy for glaucoma.