Recapitulation of the two-cell visual cycle in photoreceptors and its effects on retinoid flux and remedy of toxic retinoid species

光感受器中双细胞视觉周期的概括及其对类视黄醇通量的影响以及有毒类视黄醇种类的补救

• 批准号: 10609438
• 负责人: Zachary John Engfer
• 金额: $ 4.25万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609438
• 关键词: 11 cis Retinal; 11-cis-Retinol; Affect; Age; All-Trans-Retinol; Back; Binding; Biochemical; Biochemical Pathway; Biochemistry; Blindness; Brain; Cell Death; Cells; Chemicals; Chronic; Cone; Coupled; Coupling; Darkness; Defect; Degenerative Disorder; Disease; Electrophysiology (science); Electroretinography; Engineering; Enzymes; Esters; Ethanolamines; Eye; Fatty Acids; Functional disorder; Future; Genetic; Health; Helper-Inducer T-Lymphocyte; High Pressure Liquid Chromatography; Human; Immunohistochemistry; Immunology; Isomerism; Kinetics; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Knowledge; Lasers; Lead; Light; Link; Molecular; Molecular Biology; Molecular Evolution; Morphology; Muller' s cell; Mus; Natural regeneration; Ophthalmoscopy; Opsin; Optic Nerve; Optical Coherence Tomography; Patients; Phenotype; Photoreceptors; Phototransduction; Physiological; Pigments; Proteins; Quality of life; RPE65 protein; Reaction; Recycling; Regenerative pathway; Research Technics; Resistance; Retina; Retinal Degeneration; Retinal Diseases; Retinal Dystrophy; Retinal Pigments; Retinal dehydrogenase; Retinoids; Retinol dehydrogenase; Rod; Scanning; Signal Transduction; Structure of retinal pigment epithelium; Supporting Cell; Testing; Therapeutic; Therapeutic Intervention; Training; Travel; Vertebrate Photoreceptors; Vision; Visual; Visual Fields; Visual impairment; Work; cell killing; cell type; chromophore; crosslink; experience; lecithin-retinol acyltransferase; mouse model; remediation; retinal damage; retinol isomerase; sex; stem; therapeutic gene; treatment optimization; vision science; visual cycle

PROJECT SUMMARY/ ABSTRACT. Retinal degenerative (RD) diseases result in a progressive loss of vision, and have a devastating impact on a patient’s quality of life. Many genetic factors that nucleate these diseases are intricately linked to defects in the visual (retinoid) cycle. This cycle is necessary for regenerating the essential visual pigment 11-cis-retinal after it is photoisomerized to all-trans-retinal; errors in this multi-step recycling of all-trans-retinal back to 11-cis- retinal leads to the buildup of toxic retinoid photo-oxidation products that can kill photoreceptors and the supporting retinal pigment epithelium (RPE). Few therapeutic options exist for mitigating the damage that is caused by these photo-oxidation products, especially after cell death in the retina has started to affect quality of vision. Normally, the vertebrate visual cycle is distributed across two distinct cell types, the retinal pigment epithelium and the photoreceptors (i.e., rods and cones). In the functional visual cycle, 11-cis-retinal is initially bound to opsin proteins within the photoreceptors, where it is then isomerized to all-trans-retinal in the presence of light. This transformation initiates the phototransduction signaling cascade that travels through optic nerve to the brain, where the signals are integrated into a coherent visual field. The all-trans-retinal molecules are then shed by opsins and converted to all-trans-retinol by all-trans-retinal dehydrogenase. The all-trans-retinol is then transported from the photoreceptors to one of two “helper” cell types- RPE cells that support both rod and cone function, and Müller cells that solely support cones. Because RPE-linked visual cycle dysfunction has a greater impact on the retina as a whole, we’ve elected to focus on just the RPE-based visual cycle and not the cone- exclusive alternative visual cycle. When all-trans-retinol is transported from the photoreceptors to the RPE, the all-trans-retinol undergoes two key reactions; one catalyzed by lecithin-retinol acyltransferase (abbr. Lrat), and the other by retinal pigment epithelium-specific 65 kDa (abbr. Rpe65). Lrat catalyzes the coupling of all-trans retinol to fatty acids, forming stable retinyl ester intermediates. These retinyl esters are subsequently isomerized and hydrolyzed by Rpe65 to give 11-cis-retinol. 11-cis-retinol is then oxidized to 11-cis-retinal by 11-cis-retinol dehydrogenases and transported back to the photoreceptors for re-use. When the visual cycle is hindered, all-trans retinal can build up in the photoreceptors, leading to the formation of toxic photo-oxidation products that cause retinal degeneration. I intend to expand our knowledge of the visual cycle via engineered expression of Lrat and Rpe65 in the photoreceptors. In studying how manipulation of retinoid flux in the visual cycle controls the emergence and progression of RD, we can optimize therapeutic interventions that target the central drivers of retinal disease, while simultaneously reversing the toxic buildup of retinoids in chronic RD.

项目摘要/摘要。