Role of Intrinsic Neuroprotective Signaling in Diabetic Retina

Abstract: Diabetic retinopathy (DR) is a leading cause of blindness and a common complication of diabetes characterized by progressive neurovascular degeneration in the retina. Currently effective therapies that can sufficiently protect retinal neurons from cumulative diabetic damage are lacking. As such, understanding the molecular mechanisms of diabetes-induced neuronal damage and developing new treatment for DR are unmet needs. In this project, we seek to address this knowledge gap by defining the role of a multifunctional molecular chaperone namely p58IPK in retinal neurons in diabetes. Prior work has identified p58IPK as a putative regulator of eIF2α kinases and an endoplasmic reticulum (ER) chaperone participating in protein translation control and the protein folding process. Loss of function mutations of DNAJC3, which encodes p58IPK, lead to juvenile diabetes and multisystemic neurodegeneration in the central and peripheral nervous systems. In pancreatic β cells, deletion of p58IPK increases endoplasmic reticulum (ER) stress and sensitizes the cells to apoptosis; however, the mechanisms by which p58IPK deficiency causes neurodegeneration are unstudied and the exact function of p58IPK in retinal neurons under diabetic conditions remains unknown. Recently, we have obtained exciting preliminary data using our newly generated cell-specific p58IPK conditional knockout (cKO) mouse lines. Our results strongly support that p58IPK functions as an intrinsic protective molecule to maintain retinal function under stress conditions. In this project, we will define the in vivo role of p58IPK in retinal neurons during DR pathogenesis. We will investigate new molecular pathways by which p58IPK regulates protein and lipid homeostasis through the integrated stress response (ISR) and UGGT2-mediated lipid glycosylation. Finally, we will evaluate the neuroprotective effects of targeting p58IPK and its downstream pathways in the diabetic retina for developing new treatments for DR. Successful completion of the proposed studies will not only provide novel insights into diabetic retinal dysfunction and neurodegeneration, but also help advance the field in understanding the pathogenesis of p58IPK mutation-induced multisystemic neurodegeneration.