The National Eye Institute (NEI) awarded a $714,141 Project Grant under CFDA 93.867 (Vision Research) to the University of Utah to support research on hedgehog signal transduction during vertebrate eye development. The project aims to: 1) Investigate how the G protein-coupled receptor Smoothened (SMO) and its binding to protein kinase A (PKA) regulate retinal development and retinal ganglion cell differentiation in human retinal organoids; 2) Assess the impact of SMO's G protein coupling and PKA-binding pathways on ocular hedgehog signaling and eye development in a zebrafish model; and 3) Determine the atomic-level structure of the SMO/PKA complex to enable therapeutic targeting. The University of California, San Diego is a sub-awardee on this project, contributing expertise in cell biology, structural biology, and animal models of eye development. The findings from this comprehensive research program are expected to advance the development of therapeutics for debilitating eye disorders and enable more precise generation of ocular cell types for regenerative medicine.