Grant: Project Grant

Sight is essential for humans to gather critical information about their surroundings. The fear of going blind has been reported to be more powerful than that of having cancer or heart disease. Glaucoma is the leading cause of irreversible blindness, affecting >60 million people worldwide. There is no cure for glaucoma and current therapies are inadequate. Loss of vision in glaucoma results from the death of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. High intraocular pressure is the most significant risk factor for developing the disease. A challenge in the management of glaucoma is that pathological changes in these patients occur years, possibly decades, before symptoms appear. Thus, there is an unmet need for novel therapies that stimulate RGC regeneration and restore vision. One of the earliest signs of damage in glaucoma is the retraction of RGC dendrites, the fine processes that connect neurons within the retina. In an exciting recent study, we discovered that insulin promoted remarkable dendrite regeneration, restored circuit function, and extended neuronal survival in mouse glaucoma models. In this application, we will: 1) determine whether deficits in insulin signaling trigger early dendritic pathology in glaucoma, 2) elucidate molecular mechanisms that promote insulin-mediated dendrite regeneration, and 3) establish the efficacy of insulin for RGC repair and vision restoration in nonhuman primates. The proposed project is unique because it will provide critical knowledge on whether insulin signaling deficits contribute to early dendrite retraction and synapse loss, and it will elucidate molecular mechanisms driving arbor regeneration and circuit repair. Furthermore, this work is timely and important because it will provide pre-clinical validation of the efficacy of insulin in non-human primate glaucoma, which will inform the design of future human clinical trials for this indication.