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Cone Opsin-Ligand Interactions and Photoreceptor Health

视锥细胞视蛋白-配体相互作用和感光器健康

基本信息

批准号：
8678927
负责人：
MASAHIRO KONO
金额：
$ 37.17万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8678927
关键词：
11 cis Retinal Aging Agonist Animal Model Binding Biochemical Biological Biological Models Cell Culture Techniques Cell Death Cell Survival Cells Cessation of life Color vision defect Cone Data Defect Development Disease Effectiveness Electroretinography Ensure Etiology Event Eye Fluorescence Microscopy GTP-Binding Proteins Generations Genes Genotype Goals Health In Vitro Investigation Ionones Laboratories Laboratory Study Lead Leber&apos s amaurosis Ligands Light Mass Spectrum Analysis Metabolism Methods Molecular Mus Mutation Opsin Pathogenesis Patients Pattern Phosphorylation Inhibition Photoreceptors Phototransduction Post-Translational Protein Processing Prevention Process Property Proteins RPE65 protein Retina Retinal Retinal Cone Retinal Pigments Retinitis Pigmentosa Retinoids Rod Outer Segments Severities Solutions Source Stargardt&apos s disease Testing Therapeutic Therapeutic Agents Time Transducin Vertebrate Photoreceptors Vision Visual Vitamin A Wild Type Mouse Work abstracting analog base chromophore gene therapy improved in vivo Model mouse model photoreceptor degeneration prevent protein activation protein folding response restoration retinal rods small molecule trafficking vitamin A analog

项目摘要

Project Summary / Abstract The broad objective of this project is to understand the underlying events that lead to photoreceptor degeneration when problems with retinoid metabolism arise and to develop methods to prevent cones from degenerating. In Leber Congenital Amaurosis type 2 (LCA2), generation of the native chromophore of visual pigments (11-cis retinal) is inhibited. In mouse models for LCA2, cone cells die rapidly. Damage is most severe with short wavelength sensitive (SWS1) cones. This pattern roughly parallels the pathogenesis of LCA2. Studies from other laboratories have demonstrated that gene therapy can restore vision but appears limited by irreversible cone loss prior to the treatment. Early administration of an exogenous source of 11-cis retinal to mouse models improved cone survival, but recent work from this laboratory demonstrated that this was ineffective when mice were subjected to room light. These results suggest that (1) cone opsin/11-cis retinal interactions are important in preventing cone death, and (2) 11-cis retinal will not be the solution to treating LCA2 because normal light conditions negates its benefits. Because cone opsins are constitutively active but deactived with 11-cis retinal, the hypothesis for this project is that the increased levels of active cone opsins lead to cone degeneration in LCA2. Thus, light-insensitive small molecules that deactivate cone opsins will be protective to cone cells when endogenous 11-cis retinal is limited. Preliminary data indicate that beta ionone, a truncated analog of 11-cis retinal, improved survival of middle/long wavelength-sensitive (M/LWS) cones but not SWS1 cones. Consistent with the hypothesis, beta ionone is an inverse agonist to M/LWS cone opsins but an agonist to SWS1 cone opsins. This proposal aims to improve the survival of all cone types in mouse models for LCA2 such that reintroduction of the missing gene later in development can still improve vision; identify new compounds that can deactivate cone opsins; ensure that they will not severely impede vision in wild-type mice; and determine the impact of these compounds on trafficking of and post-translational modifications to cone opsins in cell culture and animal models. Fluorescence microscopy, electroretinography, mass spectrometry, and biochemicial methods will be used to assess the effects of test compounds on cone cell survival, function, and opsin properties. The use of opsin inverse agonists may have broader applicability in improving photoreceptor survival for other visual problems associated with compromised retinoid processing such as Stargardt's, retinitis pigmentosa, and aging.

项目摘要/摘要