Wednesday, April 2, 2025
4/2/2025
Retinal Circuitry - EY028927 Retinal Circuitry Project Summary Abstract This grant is constructed around 3 simple conceptual questions, with 3 specific aims generated around studying retinal circuity and how that circuitry changes in disease. The last grant period responded to a strategic goal of the NEI, and funded infrastructure and the creation of a set of connectomes to explore retinal wiring and serve as a resource for future work in pathoconnectomes for those model systems from early retinal degeneration to late retinal degeneration. Connectomes that derived from that work are a mouse retinal connectome RC2, and a non-human primate retinal connectome RC3, that are the largest, and highest resolution retinal connectomes now on Earth, encompassing all of the resolution required to resolve synapses, gap junctions, adherens junctions and more. Specific Aim 1 will explore the comparative anatomy of retinal circuit topologies from mouse, to rabbit, to non-human primate, focusing initially upon well understood retinal circuit topologies that we have worked out in rabbit such as the Aii amacrine cell, but expanding to other retinal cell classes and network topologies including directional selectivity. Specific Aim 2 proposes to build 3 new pathoconnectomes from non-human primate models of retinal disease including AMD, optic nerve atrophy, and achromatopsia, and initiate annotation in those databases, continuing the successful work initiated in the last award period with the hypothesis that the ultrastructure of neuronal circuit topology in degenerative disease points to stereotyped connections that reveal targets for therapies not just in mice and rabbits, but also in non-human primate models relevant to human disease. Specific Aim 3 will map proteins from the progressive stages of retinal degeneration in rabbit models of retinal degeneration, and virtually map them into ultrastructural space of our existing connectomes and pathoconnectomes. These changes in proteins reflect alterations in the pharmacology, morphology, metabolism, and functional circuitry that suggest additional targets for therapeutic intervention, revealed by specific protein expression and localizations, informative as to mechanisms associated with retinal degeneration and remodeling. Proteins serve as mediators of cell/cell communication and contact and their inclusion in retinal connectomes will facilitate the fundamentals of modeling.
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