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Principal Investigator: BRAD FORTUNE
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $42,854
Funding agency: National Eye Institute
PROJECT SUMMARY / ABSTRACT
During development, specific synaptic partners connect in order to ensure proper neural circuit function,
but how these connections are disassembled during neurodegeneration is less well understood. In rodent
experimental glaucoma (EG) models, synapse loss occurs early, preceding retinal ganglion cell (RGC) dendrite
retraction and cell death. Converging evidence in rodents suggests that specific RGC types are more susceptible
to elevated intraocular pressure, but little is known about retinal circuit disassembly in glaucomatous primate
retina. Indeed, significant differences in mice, which lack a lamina cribrosa and macula and have dissimilar RGC
types, limit the translation and generalizability of findings to humans. It is critically important to address this
knowledge gap in order to advance successful development of clinically relevant diagnostics and novel treatment
approaches, such as neuroprotection, gene therapy, and cell-based vision restoration strategies. Here we
assemble a highly collaborative team of investigators with complementary expertise well-matched to our goal
of systematically determining the connectivity, function, and transcriptomes of RGCs undergoing circuit
and synapse disassembly in glaucomatous primate retina. Our approach builds on a well-established rhesus
macaque non-human primate (NHP) model of experimental glaucoma that closely recapitulates structural and
functional changes observed in human glaucoma, and permits detailed and precise staging of disease. Based
on our studies in mice and preliminary data in NHP, we hypothesize that specific microcircuits in the injured
adult NHP retina may exhibit susceptibility in connectivity and function, which is reflected in differential
gene expression. To test this hypothesis, we apply rigorous quantitative electrophysiological, anatomical, and
molecular assessments focusing on the four main RGC types in NHP retina: ON and OFF midget and parasol
ganglion cells. Aim 1 will use high-density multielectrode arrays, single cell recordings, and Patch-seq to identify
the functional RGC types that are vulnerable in NHP EG and probe their transcriptomes to reveal mechanistic
insights and novel therapeutic targets. Aim 2 will determine the specificity and patterns of circuit and synapse
disassembly in NHP EG from both lamina-specific and cell type-specific perspectives using detailed circuit and
synapse mapping. The proposal is innovative because it brings together multi-modal function, morphologic, and
molecular analyses, and is significant because it focuses on the four main RGC types in primate that account for
the majority of human vision and are affected in glaucoma. We will generate significant resources for the scientific
community and reveal insights into retinal circuit disassembly and the potential for circuit repair in a highly
clinically relevant model of glaucoma.
Terms: <21+ years old><Address><Adult><Adult Human><Affect><Anatomic Sites><Anatomic structures><Anatomy><Cell Body><Cell Death><Cells><Communities><DNA Therapy><Data><Dendrites><Development><Diagnostic><Differential Gene Expression><Disease><Disorder><Early Diagnosis><Early treatment><Electrophysiology><Electrophysiology (science)><Ensure><Exhibits><Experimental Models><Eye><Eyeball><Gene Transfer Clinical><Genetic Intervention><Glaucoma><Goals><Human><Injury><Intraocular Pressure><Investigators><Knowledge><M mulatta><M. mulatta><Macaca mulatta><Maps><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Analysis><Morphology><Murine><Mus><Nerve Degeneration><Neuron Degeneration><Neurophysiology / Electrophysiology><Ocular Tension><Patients><Pattern><Physiologic Intraocular Pressure><Predisposition><Primates><Primates Mammals><Research Personnel><Research Resources><Researchers><Resources><Retina><Retinal Ganglion Cells><Rhesus Macaque><Rhesus Monkey><Rodent><Rodentia><Rodents Mammals><Sight><Specificity><Staging><Structure><Susceptibility><Synapses><Synaptic><Testing><Tissue-Specific Differential Gene Expression><Tissue-Specific Gene Expression><Translating><Translations><Vision><adulthood><cell type><clinical development><clinical relevance><clinically relevant><density><developmental><early detection><early therapy><electrophysiological><gangliocyte><ganglion cell><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genomic therapy><glaucomatous><global gene expression><global transcription profile><improved><injured><injuries><innovate><innovation><innovative><insight><intra-ocular pressure><macula><macular><multi-electrode arrays><multi-modality><multielectrode arrays><multimodality><necrocytosis><neural circuit><neural circuitry><neural degeneration><neurocircuitry><neurodegeneration><neurodegenerative><neurological degeneration><neuronal degeneration><neuroprotection><neuroprotective><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><non-human primate><nonhuman primate><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><patch sequencing><patch-seq><patchseq><preservation><repair><repaired><restore sight><restore vision><retinal ganglion><sight restoration><synapse><synaptic circuit><synaptic circuitry><transcriptome><translation><vision restoration><visual function>