PROJECT SUMMARY Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. A pivotal aspect of early ROP is an arrest in physiologic retinal vascular development. The retinal avascularity and consequent hypoxia leads to proliferative blinding neovascularization (NV). Ischemia induces retinal cell dysfunction and irreversible cell damage. NV aggravates vision deterioration. However, current clinical standard-of-care targeting abnormal retinal NV does not improve and may even impair vision. The driving concept in this proposal is to create a favorable retinal environment for cell survival, vascular repair and revascularization of ischemic retina. Multiple retinal cell types participate in shaping retinal environment, including vascular endothelial cells (ECs), retinal myeloid elements/microglia/macrophages (RMCs), and neuronal elements such as retinal photoreceptor cells (PRCs) and retinal ganglion cells (RGCs). The underlying mechanisms for these cellular and molecular activities remain poorly defined. Sigma 1 Receptor (Sig1R), a unique molecular chaperone, offers a novel approach to favorably enhance the retinal environment under disease states. Activation of Sig1R provides protection against two major facets of the ischemic retina: oxidative stress and inflammation. The PI’s previous research indicated powerful retinal neuroprotection of Sig1R in retinal neurodegenerative diseases. Sig1R activation showed profound neuroprotection in retinal neurons including PRCs and RGCs. Most-recent independent research by the PI has explored the role of Sig1R in retinal vascular diseases including ROP. The PI’s preliminary data showed that: i) activation of Sig1R by its ligand (+)-pentazocine ((+)-PTZ) can markedly protect against avascularity and NV in oxygen-induced retinopathy (OIR, model of ROP); ii) (+)-PTZ administration significantly rescues impaired visual function in OIR mice; iii) (+)-PTZ treatment inhibits the release of proinflammatory and proangiogenic factors in OIR retina; iv) Sig1R knockout delays retinal vascular development at postnatal day 3. The next steps to assess this promising bi-functional (vascular and neuronal) therapeutic potential will be to characterize the novel role of Sig1R in retinal normal vascular development and vascular damage in OIR model, and further to identify which cell types/molecules are modulated/targeted by Sig1R in its reprogramming of the retinal response to ischemia in OIR. I propose to test the hypothesis that Sig1R acts as a novel key modulator of normal retinal vascular development and neurovascular damage in OIR, limits vascular injury by promoting reparative microglia/macrophages via inhibition of proinflammatory and proangiogenic factors, and provides a novel neurovascular therapy for ROP. We propose three specific aims. 1) Characterize the role of Sig1R in normal retinal vascular development and vascular damage in OIR model. 2) Test the hypothesis that Sig1R limits vascular injury by pr...