PROJECT SUMMARY Optic nerve regeneration holds potential for restoring vision for millions of patients with glaucoma and other optic neuropathies, currently the world's leading cause of irreversible blindness. RGC replacement poses a formidable challenge because RGCs represent a heterogeneous class of projection neuron spanning great distances while encoding precisely compartmentalized features of visual stimuli. Vision restoration in optic neuropathy necessitates restoring RGC connectivity both within the retina and at multiple retinothalamic targets. While major advancements have been made in attaining regeneration of portions the RGC pathway in isolation, translating these discoveries to viable clinical therapies that target the entire RGC pathway requires collaborative multidisciplinary teams to discuss approaches, share data, and unify protocols. We propose to jumpstart this process by bringing together a group of ~150 investigators with diverse backgrounds and scientific expertise to solve the most pressing questions in optic nerve regeneration. The Retinal ganglion cell Repopulation, Stem cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Workshop will assemble ~150 leading and emerging vision scientists to 1) define and prioritize the most critical challenges and questions related to regenerative medicine for optic nerve disease over the next 5 years and 2) brainstorm innovative tools and experimental approaches to meeting these challenges while fostering opportunities for collaborative scientific investigation among diverse investigators. Collaborative development will occur in three phases. Participants will self-select 5 discussion sections, each co-moderated by a team of senior & junior investigators: 1) RGC development & differentiation; 2) Transplantation methods & models; 3) RGC survival & host interactions; 4) Inner retinal wiring; and 5) Brain connectivity. In Phase I, participants will delineate the most important questions and challenges hindering clinical translation of vision restoration treatments for optic neuropathy, by engaging in a 4-month long virtual discussion that involves iterative, inclusive, consensus building. In Phase II, participants will meet at the RReSTORe workshop to share ideas, insights, and data in a collaborative roundtable discussion to identify tools, models, and experiments that will propel clinical translation of vision restoring optic neuropathy treatments. In Phase III, participants will establish a sustainable, collaborative investigator network that will advance the RGC replacement field, with an emphasis on maximizing diversity of participants. A web-based collaborative platform, facilitating discussions and debriefings, will follow the RReSTORe workshop. A discussion board for conversations and a quarterly webconference will be established and actively moderated indefinitely. We aim to lay the foundation for a large, sustainable, interdisciplinary consortium of investigators from di...