Abstract: Diabetic retinopathy is a common complication of diabetes characterized by progressive neurovascular injury and the consequent retinal function deterioration. Currently there are no therapies that can effectively protect retinal neurons, and thereby mitigate, or reverse, the visual dysfunction in diabetic patients. Developing such therapies is an urgent and unmet need for the field. In the previous funding period, we identified that X-box binding protein 1 (XBP1), a stress-inducible transcription factor, plays a central role in retinal cell adaptation to chronic stressors in aging and diabetes. Conditional knockout (cKO) of XBP1 in the retina results in accelerated retinal function decline, loss of retinal neurons, disruption of synapses, and aberrant microglia activation in the retina with aging. Importantly, we found that XBP1 expression in the aging retina is gradually decreased and activation of XBP1 in response to endoplasmic reticulum (ER) stress is reduced. We reasoned