PROJECT SUMMARY Pericytes and myeloid cells cooperate with endothelium to orchestrate formation of a properly branched, functional vessel network that sustains retinal function and thereby enables vision. Disrupted communication between endothelium, pericytes and myeloid cells leads to excessive and pathological angiogenesis in ocular neovascular diseases (ONDs) such as advanced age-related macular degeneration and diabetic retinopathy that cause vision loss in millions of Americans. Excessive angiogenesis is currently treated by inhibition of a single factor VEGF that targets endothelial cells only. In this proposal we identify a novel SLIT2-ROBO1&2 ligand- receptor pathway that promotes retinal neovascularization through direct receptor signaling effects in pericytes and myeloid cells. By targeting pericytes and myeloid cells, ROBO inhibition in ONDs may confer additional benefit over VEGF inhibition of ECs alone. We will define the molecular basis of SLIT2-ROBO1&2 signaling and its biological role in pericytes and myeloid cells to uncover novel biology controlling retinal development and homeostasis that could be applied to OND prevention.