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Principal Investigator: Ryoji Amamoto
Organization: MASSACHUSETTS EYE AND EAR INFIRMARY
Fiscal Year: 2024
Award: $135,755
Funding agency: National Eye Institute
Project Summary
Retinitis Pigmentosa (RP) is an inherited retinal disease afflicting 1 in 4,000 people worldwide. The disease
progresses initially by rod photoreceptor degeneration caused by mutations in rod-specific genes, although
different mutations in different genes converge upon the same rod degeneration phenotype in this disease.
However, it is the subsequent cone photoreceptor degeneration that causes loss in daylight color vision and
ultimately, diminishing quality of life for most patients. While gene therapy to replace a mutated gene with a
functional copy has been successful, given the heterogeneity in mutations and genes, it is difficult to treat all RP
cases by targeting the rods. Instead, a generic therapy to preserve the cones upon rod degeneration may lead
to a more comprehensive therapeutic option. Despite progress, the molecular mechanism for this secondary
cone degeneration remains unclear. The goal of this proposed research is to determine whether the breakdown
of the Blood-Retina-Barrier (BRB) plays a causal role in non-cell-autonomous cone death in RP. During the
independent phase of this grant (R00 phase), we will explore the effect of removing the intra-retinal vasculature
on cone survival (Aim 1) and identify the foreign protein and cells that infiltrate the retina upon BRB breakdown
(Aim 2). Completion of the proposed aims will lead to the identification of key regulators of cone survival in mouse
models of RP. Moreover, we may identify, for the first time, a causal relationship between BRB breakdown and
secondary cone death, opening new cellular targets to prevent cone loss in patients with RP. Long-term, the
approaches outlined in this grant can become the cornerstone for answering questions regarding how, in general,
neurons and other supporting cells degenerate in neurodegenerative disorders across the central nervous
system. The rigorous scientific training received during the K99 phase in the Cepko Lab at Harvard Medical
School built a strong foundation for an independent career investigating the molecular mechanisms of retinal
degeneration.
Terms: <7S Gamma Globulin><Abscission><Age><Antibodies><Blindness><Blood><Blood - brain barrier anatomy><Blood Reticuloendothelial System><Blood Vessels><Blood-Brain Barrier><Blood-Retinal Barrier><Body Tissues><CNS Nervous System><Causality><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Central Nervous System><Cessation of life><Choroid><Color Visions><Cone><Cone Photoreceptors><Cytotoxic cell><DNA Therapy><Death><Degenerative Neurologic Disorders><Detection><Dextrans><Disease><Disease Progression><Disorder><Etiology><Excision><Exhibits><Extirpation><Extravasation><Ferroprotoporphyrin><Foundations><Future><Gene Transfer Clinical><Genes><Genetic Alteration><Genetic Change><Genetic Intervention><Genetic defect><Genotype><Goals><Grant><Hemato-Encephalic Barrier><Heme><Hereditary><Heterogeneity><Human><IgG><Immune><Immune infiltrates><Immunes><Immunofluorescence><Immunofluorescence Immunologic><Immunoglobulin G><Infiltration><Inherited><Intracellular Communication and Signaling><K lymphocyte><Leakage><Link><Literature><Mice><Mice Mammals><Modern Man><Molecular><Murine><Mus><Mutate><Mutation><NK Cells><Natural Killer Cells><Nerve Cells><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neuraxis><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurons><Patients><Peripheral><Permeability><Persons><Phase><Phenotype><Pigmentary Retinopathy><Play><Proteins><Protoheme><QOL><Quality of life><Removal><Research><Retina><Retinal Blood Vessels><Retinal Cone><Retinal Degeneration><Retinal Diseases><Retinal Disorder><Retinal Vessels><Retinitis Pigmentosa><Rod><Rod Photoreceptors><Role><Sight><Signal Transduction><Signal Transduction Systems><Signaling><Spillage><Supporting Cell><Surgical Removal><Tapetoretinal Degeneration><Therapeutic><Time><Tissues><Tracer><Training><Vision><Weight><Work><ages><biological signal transduction><bloodbrain barrier><career><causation><cell type><cellular targeting><cone cell><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><degenerative retina diseases><dextran><disease causation><experiment><experimental research><experimental study><experiments><ferroheme><gene repair therapy><gene replacement therapy><gene therapy><gene-based therapy><genetic therapy><genome mutation><genomic therapy><human disease><immune cell infiltrate><medical college><medical schools><mouse model><murine model><nerve cell death><nerve cell loss><neurodegenerative illness><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><photoreceptor degeneration><postnatal><preservation><prevent><preventing><resection><retina blood vessel structure><retina degeneration><retina disease><retina disorder><retinal degenerative><retinal degenerative diseases><retinal rods><retinopathy><rod and cone dystrophy><rod cell><rod-cone dystrophy><role model><school of medicine><social role><success><therapeutic target><vascular><vision loss><visual function><visual loss><weights>