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Formation of Retinyl-Opsins by Retinyl Formate as Molecular Shades Against Light-Induced Retinal Damage

视黄基甲酸形成视黄基视蛋白作为抗光诱导视网膜损伤的分子色调

基本信息

批准号：
10390090
负责人：
John Dong-Hoon Hong
金额：
$ 4.22万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-24 至 2026-01-23
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10390090
关键词：
11 cis Retinal Adolescent Affect Age Age related macular degeneration All-Trans-Retinol American Attenuated Back Binding Biological Assay Blindness Bruch&apos s basal membrane structure Child Complex Contact Lenses Dangerousness Deposition Development Dimerization Disease Dose Drusen Electroretinography Exposure to Eye Future Genes High Pressure Liquid Chromatography Histology Impairment Individual Inherited Knock-out Lasers Legal Blindness Light Lipids Lipofuscin Macular degeneration Measures Mediating Membrane Membrane Transport Proteins Mind Modification Molecular Molecular Conformation Morphology Mus Mutation Nuclear Ophthalmoscopy Opsin Optical Coherence Tomography Oxidoreductase Patients Phenotype Photoreceptors Phototransduction Physical condensation Pre-Clinical Model Production Property Proteins Quality of life Retina Retinal Photoreceptors Retinal Pigments Retinitis Pigmentosa Retinoids Rhodopsin Rod Outer Segments Scanning Site Stargardt&apos s disease Structure of retinal pigment epithelium Testing Therapeutic Intervention Thick Visible Radiation Vision Work absorption adduct alpha Subunit Transducin analog chromophore crosslink dimer in vivo inhibitor macula mouse model neuroprotection oxidative damage prevent retinal damage success translocase visual cycle

项目摘要

Project Summary/Abstract Stargardt disease (STGD1) is the most common form of inherited juvenile macular degeneration. STGD1 is caused by autosomal recessive mutations in the ABCA4 gene, which encodes a membrane transporter that removes all-trans-retinals (atRALs) from photoreceptors as part of the retinoid cycle. Free atRALs or their bisretinoid condensation products promote photo-oxidative damage to the macula as seen in STGD1. The same atRAL-mediated damage can also be seen in age-related macular degeneration (AMD), which is expected to affect at least 18 million Americans by 2050. The production of atRAL starts at the level of opsin proteins, which reside within photoreceptor outer segment disc membranes. Light is captured by opsin- chromophore complexes, or visual pigments, causing their native bound chromophore, 11-cis-retinal (11cRAL), to be converted to atRAL and forming activated opsins. These activated opsins initiate phototransduction and are eventually spontaneously hydrolyzed to apo-opsin and atRAL. Exposure to intense light causes photoreceptor overstimulation and dangerously high levels of atRAL, potentially leading to photoreceptor damage and loss. Recently, a chromophore analogue, retinyl formate (RF), was found to irreversibly bind apo- opsin and form retinyl-opsins that can no longer form visual pigments with 11cRAL. These retinyl-opsins also absorb light outside the visible light spectrum and do not subsequently release atRAL upon light absorption. Thus, RF can potentially reduce the proportion of visual pigments in the retina and thereby reduce the atRAL burden during periods of intense light exposure. Therefore, I hypothesize that RF can serve as a molecular shade at the opsin level, providing long-lasting protection to photoreceptors from light-induced damage. In this proposal, I will characterize the site of the retinyl modification on opsin by RF, distinguishing whether RF binding is competitive or allosteric with 11cRAL. I will determine if and how retinyl-opsins also could initiate the phototransduction cascade. To investigate its applicability to a pre-clinical model, I will study whether RF treatment of an STGD1 mouse model provides neuroprotection to photoreceptors against intense light exposure via formation of retinyl-opsins and reduction of retinal atRAL and determine the relative proportion of retinyl-opsins and remaining natural visual pigments. This work thus serves as a proof-of-concept approach to determining whether disabling a proportion of opsins with an irreversible inhibitor of visual pigment formation could prevent light-induced damage to photoreceptors, and point to the development of future therapeutics and interventions for STGD1 and AMD.

项目总结/文摘