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

摘要 IRBP的表达比视觉周期中任何假定作用所需的时间要早得多。在上一次拨款中 周期中，我们证明了IRBP在早期视网膜发育中是必需的，因为没有它，我们检测到了形态 与杆状和球果的末端分化和外节的早熟发育相一致的变化 丛状层。 与此同时，我们发现眼睛过度生长和光轴伸长明显始于 P7。这意味着IRBP在控制眼睛生长方面发挥了作用，即使没有基于视觉的信号。 我们现在知道，IRBP丢失会导致各种严重的眼病，包括深度近视和视网膜 变性，我们最近发现了迟缓的瞳孔光反射(PLR)。 在最近的人类GWAS研究中，IRBP基因多态与屈光不正和角膜相关 曲率。先前的关联研究证实，IRBP缺陷会导致合并的RP和严重近视。 我们认为IRBP缺乏的异常与影响眼睛正常测定的眼部疾病有关 大小，基于果蝇发育生物学以前和同时进行的强大和丰富的工作 眼睛和器官大小的命运。我们测试了在IRBP中调节大小决定的相同的五个主要途径 出类拔萃的眼睛。 我们试图了解近视、RD和IRBP中其他异常之间的假定等级关系 突变。为此，我们构建并验证了一种新的条件基因敲除(KO)小鼠和一种新的 传统的KO。在这里，我们使用它们来整理时间、空间和机械关系，这些关系导致 这三大症状。最后，我们在IRBP中测试已知的减缓近视或器官大小的药物的疗效-/- 模型询问他们在减少任何或所有IRBP缺乏症状方面是否有效。

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.