Retinoids in Vision

视黄醇在视觉中的作用

• 批准号: 9762929
• 负责人: Philip David Kiser
• 金额: $ 44.17万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762929
• 关键词: 11 cis Retinal; 9-cis-retinal; Ablation; Acetates; Affect; All-Trans-Retinol; Alleles; Animal Genetics; Animal Model; Basic Science; Binding; Bioavailable; Biochemical; Biochemical Process; Blindness; CRISPR Therapeutics; Cell Culture Techniques; Cells; Chemicals; Chemistry; Chitosan; Cone; Consumption; Crystallization; Dark Adaptation; Defect; Degenerative Disorder; Development; Disease; Dose; Drosophila genus; Embryo; Environmental Risk Factor; Enzymatic Biochemistry; Enzymes; Eye; Family; Genes; Genetic; Genetic Diseases; Genetic Engineering; Guide RNA; Human; Inherited; Intervention; Invertebrates; Isomerase; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Learning; Lecithin; Link; Metabolic; Molecular; Muller' s cell; Mus; Mutation; Natural regeneration; Nonsense Mutation; Opsin; Oral; Oral Administration; Oxidoreductase; Pathogenicity; Pathway interactions; Patients; Pharmacology; Phenotype; Phototransduction; Pigments; Procedures; Production; Proteins; Publications; RPE65 protein; Reaction; Regimen; Retina; Retinal; Retinal Cone; Retinal Degeneration; Retinal Diseases; Retinoic Acid Receptor; Retinoids; Retinol dehydrogenase; Role; Schiff Bases; Solubility; Specificity; Structure; Supplementation; Syndrome; System; Technology; Testing; Therapeutic; Toxic effect; Transferase; Translating; Treatment Efficacy; Vertebrate Photoreceptors; Vision; Visual; adduct; age related; analog; base; chromophore; clinical development; combat; design; early onset; efficacy testing; functional improvement; genome editing; improved; in vitro Assay; in vivo; knockout gene; molecular modeling; mouse model; next generation; novel; novel therapeutics; pi bond; preservation; prevent; reconstitution; retinal regeneration; retinal rods; retinol isomerase; translational research program; virtual; vision development; visual cycle

ABSTRACT A substantial proportion of retinal degenerative diseases are known to be associated with either defects in the retinoid (visual) cycle or abnormalities in retinal clearance. Thanks to painstaking biochemical reconstitution studies supported by genetically engineered animal models and genetic/phenotypic studies of humans with specific blinding diseases, a molecular understanding of the retinoid cycle and phototransduction pathway in the mammalian retina has advanced considerably over the past few years. Nevertheless, many important details regarding chemical transformations of retinal and its derivatives are not well defined and many proteins involved in 11-cis-retinal regeneration still await structural, biochemical and functional characterization. Understanding the fundamental biochemical processes underlying these diseases is essential for the development of effective therapeutics. This proposal aims to significantly improve our knowledge of molecular transformations within the retinoid cycle in vivo and then test the efficacy of novel chemical compounds that could prevent or modulate retinal degeneration. First, we will identify next-generation all-trans-retinal trapping agents. We posit that all-trans-retinal and adduct toxicity could be lowered by rapidly and reversibly forming a Schiff base with a test compound and that novel compounds identified from our structural studies could achieve this objective. To support this project, structures of the retinoid isomerase (RPE65) and lecithin:retinol acyl transferase (LRAT) determined in our laboratory will be critical. Second, we will clarify the role of RDH10 in the eye by using a cell-specific knockout of this gene. Achieving this aim will advance our understanding of the specificities of the whole RDH family aided by the crystal structure of a homologous RDH recently obtained in our laboratory. Improved characterization of the molecular specificity of the RDH family should allow us to identify additional visual cycle modulators. Third, we will test cell-specific 9-cis-retinal delivery to cones through the use non-isomerizable-locked retinal analogs that selectively bind rod opsin. We have already demonstrated that mechanism-based pharmacological interventions can restore vision in otherwise incurable genetic retinal degenerations and further improvements are possible. Finally, we will apply RNA-guided genome editing strategies to combat inherited retinal degenerative disorders driven by loss of retinoid cycle activity.

摘要 已知相当大比例的视网膜变性疾病与以下任一者相关： 类维生素A（视觉）周期缺陷或视网膜清除异常。多亏了煞费苦心的 由基因工程动物模型支持的生化重建研究， 对患有特定致盲疾病的人进行遗传/表型研究， 在哺乳动物视网膜中，类维生素A循环和光转导途径的研究已经取得进展， 在过去的几年里，然而，许多关于化学的重要细节 视网膜及其衍生物的转化还没有很好地定义，许多蛋白质参与了视网膜的转化。 11-顺式-视网膜再生仍然等待结构、生物化学和功能表征。 了解这些疾病背后的基本生化过程是必不可少的， 开发有效的治疗方法。 该建议旨在显着提高我们的知识分子转化内 体内维甲酸循环，然后测试新化合物的功效， 或调节视网膜变性。首先，我们将确定下一代全反式视网膜陷获 剂.我们认为，全反式视网膜和加合物的毒性可以降低迅速， 与测试化合物可逆地形成席夫碱，并且从所述化合物鉴定的新化合物 我们的结构研究可以达到这个目的。为了支持这个项目，维甲酸的结构 异构酶（RPE 65）和卵磷脂：视黄醇酰基转移酶（LRAT）的测定， 要批判。其次，我们将通过使用细胞特异性敲除来阐明RDH 10在眼睛中的作用。 这个基因。实现这一目标将促进我们对整体的具体性的理解。 RDH家族的帮助下，最近获得的同源RDH的晶体结构，在我们的 实验室RDH家族的分子特异性的改进表征应该允许 我们来确定额外的视觉周期调节剂。第三，我们将测试细胞特异性9-顺式-视网膜 通过使用选择性结合的非异构化锁定的视网膜类似物递送至视锥细胞 视杆细胞我们已经证明，基于机制的药物干预 可以恢复视力，否则无法治愈的遗传性视网膜变性和进一步改善 是可能的。最后我们将 应用RNA指导的基因组编辑策略来对抗遗传性 由类维生素A循环活性丧失引起的视网膜变性疾病。