Ocular Growth, Emmetropia, and Interphotoreceptor Retinoid-Binding Protein (IRBP)

眼睛生长、正视眼和感光器间视黄醇结合蛋白 (IRBP)

• 批准号: 9769038
• 负责人: JEFFREY H BOATRIGHT
• 金额: $ 43.68万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769038
• 关键词: Affect; Binding; Biochemical Pathway; Buffers; Cessation of life; Chemicals; Cornea; Defect; Development; Developmental Biology; Disease; Drops; Drosophila eye; Drug Targeting; Environmental Risk Factor; Eye; Eye diseases; FDA approved; Fatty Acids; Genes; Genetic Polymorphism; Genetic Risk; Grant; Growth; Health; Human; Human Genome; Knock-out; Knockout Mice; Knowledge; Lead; Learning; Length; Light; Light Cell; Modeling; Morphology; Mus; Mutant Strains Mice; Mutation; Myopia; Neurotoxins; Optics; Organ Size; Other Genetics; Outcome Measure; Pathology; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Population; Protein Deficiency; Proteins; Pupil light reflex; Refractive Errors; Regulator Genes; Regulatory Pathway; Retina; Retinal Degeneration; Retinoids; Role; Signal Transduction; Symptoms; Testing; Time; Vertebrate Photoreceptors; Vision; Work; base; differential expression; disabling symptom; drug efficacy; drug testing; efficacy testing; genetic linkage analysis; genetic pedigree; genome wide association study; human subject; innovation; interstitial retinol-binding protein; outer plexiform layer; prevent; reduce symptoms; response; small molecule; visual cycle

SUMMARY IRBP is expressed much earlier than needed for any putative role in the visual cycle. In the previous grant cycle, we showed that IRBP is needed in early retina development, as without it we detected morphological changes coincident with terminal differentiation of rods and cones, and precocious development of the outer plexiform layer. At the same time, we discovered excessive eye growth and elongation of the optical axis starting distinctly at P7. This implies a role for IRBP in controlling eye growth even without vision-based signaling. We now know that IRBP loss causes diverse and severe eye diseases including profound myopia and retinal degeneration, and we recently discovered sluggish pupillary light reflexes (PLRs). In recent human GWAS studies, IRBP polymorphisms are associated with refractive error and corneal curvature. Previous linkage studies established that IRBP defects caused combined RP and severe myopia. We view abnormalities of IRBP deficiency in the context of eye disease that affect normal determination of eye size, based on strong and abundant previous and concurrent work in developmental biology of the Drosophila eye and organ size fate. We test the same five principal pathways that regulate size determination in the IRBP knockout eye. We seek to understand posited hierarchical relationships among myopia, RD, and other abnormalities in IRBP mutations. To do that we have constructed and validated a new conditional knockout (KO) mouse and a new traditional KO. Here we use them to sort out the temporal, spatial, and mechanistic relationships that cause these three major symptoms. Last, we test efficacy of drugs known to slow myopia or organ size, in the IRBP-/- model asking if they are effective in reducing any or all IRBP deficiency symptoms.

总结 IRBP的表达早于视觉周期中任何假定作用所需的时间。在上一次赠款中， 周期，我们表明IRBP是需要在早期视网膜发育，因为没有它，我们检测形态 这些变化与视杆细胞和视锥细胞的终末分化以及外胚层的早熟发育相一致 网状层 与此同时，我们发现过度的眼睛生长和光轴的延长明显开始于 P7。这意味着IRBP在控制眼睛生长中的作用，即使没有基于视觉的信号。 我们现在知道，IRBP缺失会导致各种严重的眼部疾病，包括深度近视和视网膜病变。 退化，我们最近发现瞳孔对光反射（PLRs）迟缓。 在最近的人类GWAS研究中，IRBP多态性与屈光不正和角膜炎相关。 曲率先前的连锁研究确定IRBP缺陷导致RP和严重近视的组合。 我们认为IRBP缺乏症的异常在眼睛疾病的背景下，影响眼睛的正常决定， 大小，基于强大和丰富的先前和同时在果蝇发育生物学方面的工作 眼睛和器官大小的命运我们测试相同的五个主要途径，调节大小的决定，在IRBP 迷人的眼睛 我们试图了解近视，RD和IRBP中其他异常之间的假定层次关系 突变。为此，我们构建并验证了一种新的条件性敲除（KO）小鼠和一种新的 传统KO在这里，我们使用它们来整理时间，空间和机械关系，导致 这三大症状。最后，我们在IRBP-/-中测试了已知减缓近视或器官大小的药物的功效。 模型询问他们是否有效地减少任何或所有IRBP缺乏症症状。