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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：
7634989
负责人：
MASAHIRO KONO
金额：
$ 36.88万
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 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7634989
关键词：
11 cis Retinal Age Agonist Animal Model Animals Back Binding Blindness Boston Cells Cessation of life Chemicals Data Detection Disease Effectiveness Electrophysiology (science)Electroretinography Ensure Eye diseases Fluorescence Microscopy Funding Generations Goals Health Human Immunohistochemistry Knock-out Laboratories Leber&apos s amaurosis Libraries Life Ligands Light Maintenance Measures Microspectrophotometry Molecular Molecular Conformation Morphology Mus Mutation Opsin Patients Pattern Photons Photoreceptors Pigments Play Proteins RPE65 protein Recovery Retina Retinal Retinal Cone Retinal Pigments Retinaldehyde Retinoids Role Salamander Severities Testing Therapeutic Agents Tigers Toxic effect Transducin Universities Vertebrate Photoreceptors Vision Visual Visual Acuity Vitamin A Work analog base chromophore design disease phenotype early childhood early onset gene therapy insight meetings mouse model prevent research study restoration rho success treatment duration

项目摘要

The broad objective of this project is to prevent cone photoreceptors from degenerating. In a disease such as Leber Congenital Amaurosis (LCA), the levels of the native chromophore, ii-cis retinal, for visual pigments is absent or highly reduced. Vision is impaired not only because of a lack of visual pigment generation but also because cone photoreceptors are lost. In a mouse models for LCA, cone visual pigment proteins (opsins) are highly mislocalized and cone cells subsequently die. Damage seems to be most severe with blue cones. This pattern appears to parallel the pathogensis of LCA. Treating these mice with ii-cis retinal at an early age in the dark preserves healthier cones, suggesting that opsin's binding of ii-cis retinal is an important step in preventing cone death. A drawback to 11- cis retinal itself as a therapeutic agent is that it is destroyed once it combines with the opsin and exposed to light. The working hypothesis for this proposal is that in the absence of the native chromophore, chemical compounds that can mimic the effects that ii-cis retinal has on the cone opsins will also mimic the cellular effects on the cone photoreceptors. The main advantage of such compounds is that the treatment period will not require constant dark conditions. At the molecular level, cone opsins are constitutively active, and ii-cis retinal deactivates the opsins. A library of compounds that are analogs of ii-cis retinal will be tested for their effectiveness in turning off human cone opsins as judged by their abilities to activate transducin. Compounds that effectively deactivate the opsins will then be tested in isolated cone photoreceptor cells to ensure they are not toxic to cells and they are able to deactivate cone opsins inside a living cell. Compounds found to meet these criteria will be tested in 2 mouse models of LCA to determine if they can prevent the rapid degeneration of cone photoreceptor cells as judged by fluorescence microscopy and electroretinography. The ability to preserve the viability of cone photoreceptor celis in those afflicted with LCA will be a critical step to restoring visual acuity.

该项目的总体目标是防止视锥细胞退化。在一种疾病中例如莱伯先天性黑蒙 (LCA)，天然发色团 ii-cis 视网膜的水平，对于视觉色素不存在或高度减少。视力受损不仅是因为视力不足色素的产生也是因为视锥细胞感光细胞的丧失。在 LCA 小鼠模型中，锥体视觉色素蛋白（视蛋白）高度错误定位，视锥细胞随后死亡。损害蓝色视锥细胞的情况似乎最为严重。这种模式似乎与 LCA 的发病机制相似。在黑暗中对这些小鼠进行早期的 ii-cis 视网膜治疗可以保留更健康的视锥细胞，这表明视蛋白与 ii-cis 视网膜的结合是防止视锥细胞死亡的重要一步。 11的一个缺点- 顺式视网膜本身作为一种治疗剂，一旦与视蛋白结合就会被破坏，暴露在光线下。该提案的工作假设是，在没有本地人的情况下发色团，可以模拟 ii-cis 视黄醛对视锥细胞影响的化合物视蛋白还将模拟细胞对视锥细胞的影响。此类的主要优点化合物的优点是治疗期间不需要持续的黑暗条件。在分子水平上，视锥细胞视蛋白具有组成性活性，而 ii-顺式视网膜则使视蛋白失活。化合物库将测试 ii-cis 视网膜类似物关闭人视锥细胞视蛋白的有效性根据它们激活转导蛋白的能力来判断。有效灭活视蛋白的化合物将然后在分离的视锥细胞中进行测试，以确保它们对细胞没有毒性，并且它们是能够使活细胞内的视锥细胞失活。被发现满足这些标准的化合物将被在 2 个 LCA 小鼠模型中进行测试，以确定它们是否可以防止视锥细胞快速退化通过荧光显微镜和视网膜电图判断感光细胞。有能力保留患有 LCA 的视锥细胞的活力将是关键一步恢复视力。