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：
10560484
负责人：
John Dong-Hoon Hong
金额：
$ 4.38万
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/10560484
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 Darkness Deposition Development Dimerization Disease Progression Dose Drusen Electroretinography Exposure to Eye Formates Future Genes Glass High Pressure Liquid Chromatography Histology Impairment Individual Inherited Intervention Knockout Mice 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 Reaction 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 Thick Visible Radiation Vision Work absorption adduct alpha Subunit Transducin analog autosome chromophore crosslink dimer in vivo inhibitor legally blind light intensity macula mouse model neuroprotection 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.

项目摘要/摘要 Stargardt病（STGD1）是遗传少年黄斑变性的最常见形式。 STGD1是由ABCA4基因中的常染色体隐性突变引起的，该突变编码膜转运蛋白作为视网膜类似循环的一部分，从感光体中去除全反视网膜（Artrals）。自由攻击或他们的 Bistrenoid冷凝产物促进了对黄斑的光氧化损害，如STGD1所示。这在与年龄相关的黄斑变性（AMD）中也可以看到相同的ARTAR介导的损伤，这是预计到2050年将至少影响1800万美国人。蛋白质，驻留在光感受器外部片段盘膜中。光被Opsin捕获 - 发色团复合物或视觉颜料，导致其天然结合的发色团，11 cis-续订（11克），要转换为atral并形成活化的opsins。这些激活的Opsins引发了光转导和最终将自发水解为apo-oppin和artral。暴露于强烈的光原因光感受器过度刺激和危险的高水平的Artal，可能导致感光器损害和损失。最近，发现一个生色团类似物（RF），发现不可逆地结合apo- Opsin并形成视黄蛋白，无法再与11克形成视觉色素。这些视网膜粘蛋白也是如此吸收可见光光谱外的光，随后在吸收光吸收后不会释放出Atral。因此，RF可以潜在地减少视网膜中视觉色素的比例，从而减少肌肉在强烈的光线暴露期间的负担。因此，我假设RF可以用作分子 Opsin水平的阴影，为光感受器提供持久的保护，免受光诱导的损伤。在这个提案，我将通过RF来表征Opsin对Opsin修饰的位点，以区分RF 结合具有11克的竞争性或变构。我将确定视网膜粘蛋白是否以及如何发起光转导级联。为了调查其适用于临床前模型，我将研究RF是否 STGD1小鼠模型的处理可为光感受体提供神经保护剂通过形成视网膜粘蛋白的形成和减少视网膜的暴露，并确定相对比例视网膜粘蛋白和剩余的天然视觉色素。因此，这项工作是一种概念验证的方法确定是否将一定比例的Opsins用视觉色素形成的不可逆抑制剂禁用可以防止光诱导的光感受器损害，并指出未来治疗剂的发展和 STGD1和AMD的干预措施。