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: 10213728
• 负责人: JEFFREY H BOATRIGHT
• 金额: $ 42.37万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213728
• 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; conditional knockout; 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.

概括 在视觉周期中，IRBP的表达要比任何推定的角色所需的时间要早​​得多。在上一个赠款中 循环，我们表明在早期视网膜发育中需要IRBP，因为没有它，我们检测到形态学 变化与棒和锥的终末分化一致，外部的早熟发展 丛状层。 与此同时 P7。这意味着即使没有基于视觉的信号传导，IRBP也在控制眼睛生长方面发挥了作用。 我们现在知道，IRBP损失会引起多种而严重的眼部疾病，包括深远的近视和视网膜 堕落，我们最近发现了瞳孔缓慢的光反射（PLR）。 在最近的人类GWAS研究中，IRBP多态性与折射率和角膜有关 曲率。先前的连锁研究表明，IRBP缺陷导致RP和严重的近视。 我们认为IRBP缺乏症的异常在眼部疾病的情况下影响正常的眼睛确定 大小，基于果蝇发育生物学的强大和丰富的先前和同时工作 眼睛和器官尺寸的命运。我们测试了调节IRBP中尺寸确定的相同五个主要途径 敲除眼。 我们试图了解IRBP中近视，RD和其他异常之间存在的层次结构关系 突变。为此，我们已经构建并验证了一种新的条件敲除（KO）鼠标和一只新的 传统的KO。在这里，我们使用它们来整理导致的时间，空间和机械关系 这三个主要症状。最后，我们在IRBP中测试已知会减慢近视或器官尺寸的药物的功效 - / - 模型询问它们是否有效减少任何或所有IRBP缺乏症状。