Project Summary Retinopathy of prematurity (ROP) is a leading cause of vision loss in children and is currently treated by laser therapy or cryotherapy. However, both treatments destroy the peripheral vision to save the central vision with limited efficacy and do not address the underlying cause of pathological retinal neovascularization. There is no approved drug therapy for ROP in the U.S. Because vascular endothelial growth factor (VEGF) is critical to both physiological and pathological angiogenesis in ROP retinas, anti-VEGF therapy interferes with vasculogenesis and retinogenesis in premature infants, leading to adverse effects. As a result, VEGF inhibitors have safety concerns for ROP therapy. To address this urgent unmet clinical need, we recently discovered secretogranin III (Scg3) as a highly disease-restricted pro-angiogenic factor that preferentially binds to and stimulates angiogenesis of diseased but not normal vessels. This is in contrast to VEGF which indiscriminately binds to and induces angiogenesis of both diseased and normal vessels. We further developed anti-Scg3 mAbs and humanized antibodies (hAbs) to selectively inhibit pathological but not physiological angiogenesis. The critical barrier for the translation of anti-Scg3 therapy is the unknown clinical relevance of Scg3 to ROP. One of the approaches to define the clinical relevance is to identify the unknown Scg3 receptor (Scg3R) and characterize its upregulation on ROP vessels. We hypothesize that Scg3 is a clinically relevant angiogenic factor to ROP because of the marked upregulation of Scg3R in the disease condition. In Aim 1, we will use a new technique to screen and identify Scg3R. In Aim 2, we will verify Scg3R and its specific interaction with Scg3. In Aim 3, we will confirm Scg3R upregulation on ROP vs. healthy retinal vessels. The successful implementation of this project will unravel the first disease-selective ligand-receptor pair to exclusively regulate pathological but not physiological angiogenesis. Identification of Scg3R and validation of its upregulation on ROP vessels will unambiguously support the clinical relevance of anti-Scg3 therapy and facilitate the clinical translation of anti- Scg3 hAbs.